EP4225764A1 - Modulateurs du régulateur de conductance transmembranaire de la fibrose kystique - Google Patents

Modulateurs du régulateur de conductance transmembranaire de la fibrose kystique

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Publication number
EP4225764A1
EP4225764A1 EP21814947.4A EP21814947A EP4225764A1 EP 4225764 A1 EP4225764 A1 EP 4225764A1 EP 21814947 A EP21814947 A EP 21814947A EP 4225764 A1 EP4225764 A1 EP 4225764A1
Authority
EP
European Patent Office
Prior art keywords
independently selected
optionally substituted
groups independently
alkyl
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21814947.4A
Other languages
German (de)
English (en)
Inventor
Jason Mccartney
Alexander Russell Abela
Sunny Abraham
Corey Don Anderson
Vijayalaksmi Arumugam
Jaclyn CHAU
Jeremy Clemens
Thomas Cleveland
Timothy Richard Coon
Timothy A. DWIGHT
Lev Tyler Dewey Fanning
Bryan A. Frieman
Peter Grootenhuis
Anton V. Gulevich
Sara Sabina Hadida Ruah
Yoshihiro Ishihara
Haripada Khatuya
Paul Krenitsky
Vito Melillo
Mark Thomas Miller
Prasuna PARASELLI
Fabrice Pierre
Alina Silina
Joe A. Tran
Johnny Uy
Lino Valdez
Jinglan Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of EP4225764A1 publication Critical patent/EP4225764A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the disclosure relates to modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing the modulators, methods of treating CFTR mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination therapies and combination pharmaceutical compositions employing such modulators, and processes and intermediates for making such modulators.
  • CFTR Cystic Fibrosis Transmembrane Conductance Regulator
  • Cystic fibrosis is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.
  • the most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in many of the cases of cystic fibrosis and is associated with severe disease.
  • CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins.
  • epithelial cells normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
  • CFTR is composed of 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain.
  • Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na + -K + -ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl- channels, resulting in a vectorial transport.
  • One aspect of the disclosure provides novel compounds, including compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • Formula I encompasses compounds falling within the following structure: and includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; Ring B is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; V is selected from O and NH; W 1 is selected from N and CH; W 2 is selected from N and CH, provided that at least one of W 1 and W 2 is N; Z is selected from O, NR ZN , and C(R ZC ) 2 , provided that when L 2 is absent, Z is C(R ZC )
  • Formula I also includes compounds of Formula Ia: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein Ring A, Ring B, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are as defined for Formula I, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-
  • Formula I also includes compounds of Formula IIa: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein Ring B, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are as defined for Formula I, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,
  • Formula I also includes compounds of Formula IIb: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein Ring A, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are as defined for Formula I, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,
  • Formula I also includes compounds of Formula III: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein W 1 , W 2 , Z, L 1 , L 2 , R 4 , R 5 , and R YN are as defined for Formula I, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeutero
  • Formula I also includes compounds of Formula IV: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein Z, L 1 , L 2 , R 1 , R 4 , R 5 , and R YN are as defined for Formula I, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeutero)spiro
  • Formula I also includes compounds of Formula V: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein Z, L 1 , L 2 , R 4 , R 5 , and R YN are as defined for Formula I, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeutero)spiro[2.3]he
  • Formula I also includes compounds of Formula VI: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein L 1 , R 4 , R 5 , and R YN are as defined for Formula I, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-tetradeutero)spiro[2.3]hexan-5- y
  • compositions comprising at least one compound chosen from the novel compounds disclosed herein, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier.
  • These compositions may further include at least one additional active pharmaceutical ingredient.
  • the at least one additional active pharmaceutical ingredient is at least one other CFTR modulator.
  • the at least one other CFTR modulator is selected from CFTR potentiators and CFTR modulators.
  • another aspect of the disclosure provides methods of treating the CFTR- mediated disease cystic fibrosis comprising administering at least one of compound chosen from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and at least one pharmaceutically acceptable carrier.
  • the methods comprise administering a pharmaceutical composition disclosed herein, wherein the pharmaceutical composition comprises at least one additional active pharmaceutical ingredient.
  • the at least one additional active ingredient is at least one other CFTR modulator.
  • the at least one other CFTR modulator is selected from CFTR potentiators and CFTR modulators.
  • the pharmaceutical compositions of the disclosure comprise at least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, lib, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • compositions comprising at least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, lib, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may optionally further comprise (a) at least one compound chosen from (7?)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3- dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide (tezacaftor), 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropane carboxamido)-3-methylpyridin-2-yl
  • Another aspect of the disclosure provides methods of treating the CFTR-mediated disease cystic fibrosis comprising administering to a patient in need thereof at least one compound chosen from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from tezacaftor, ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, and lumacaftor.
  • additional CFTR modulating agents selected from tezacaftor, ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluor
  • compounds of the disclosure e.g., compounds of Formula I, compounds of any of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing
  • pharmaceutical compositions comprising those compounds, and optionally further comprising one or more CFTR modulating agents
  • the one or more additional CFTR modulating agents are selected from CFTR potentiators.
  • the one or more additional CFTR modulating agents are selected from CFTR correctors.
  • the one or more additional CFTR modulating agents are selected from tezacaftor, lumacaftor, ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl- 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • a further aspect of the disclosure provides intermediates and methods for making the compounds and compositions disclosed herein.
  • Tezacaftor refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)- N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5- yl)cyclopropanecarboxamide, which can be depicted with the following structure: .
  • Tezacaftor may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative.
  • Tezacaftor and methods of making and using tezacaftor are disclosed in WO 2010/053471, WO 2011/119984, WO 2011/133751, WO 2011/133951, WO 2015/160787, and US 2009/0131492, each of which is incorporated herein by reference.
  • Ivacaftor refers to N-[2,4-bis(1,1- dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, which is depicted by the structure: Ivacaftor may also be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Ivacaftor and methods of making and using ivacaftor are disclosed in WO 2006/002421, WO 2007/079139, WO 2010/108162, and WO 2010/019239, each of which is incorporated herein by reference.
  • a deuterated derivative of ivacaftor (deutivacaftor) is employed in the compositions and methods disclosed herein.
  • a chemical name for deutivacaftor is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide, as depicted by the structure: .
  • Deutivacaftor may be in the form of a further deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative.
  • Deutivacaftor and methods of making and using deutivacaftor are disclosed in WO 2012/158885, WO 2014/078842, and US Patent No.8,865,902, each of which is incorporated herein by reference.
  • “Lumacaftor” as used herein refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is depicted by the chemical structure:
  • Lumacaftor may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative.
  • Lumacaftor and methods of making and using lumacaftor are disclosed in WO 2007/056341, WO 2009/073757, and WO 2009/076142, each of which is incorporated herein by reference.
  • alkyl refers to a saturated or partially saturated, branched, or unbranched aliphatic hydrocarbon containing carbon atoms (such as, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms) in which one or more bonds between adjacent carbon atoms may be a double bond (alkenyl) or a triple bond (alkynyl). Alkyl groups may be substituted or unsubstituted.
  • haloalkyl group refers to an alkyl group substituted with one or more halogen atoms, e.g., fluoroalkyl, which refers to an alkyl group substituted with one or more fluorine atoms.
  • alkoxy refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted.
  • haloalkoxyl group refers to an alkoxy group substituted with one or more halogen atoms.
  • cycloalkyl refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12 carbons (such as, for example 3-10 carbons) and may include one or more unsaturated bonds.
  • Cycloalkyl groups encompass monocyclic, bicyclic, tricyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings.
  • Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, dispiro[2.0.2.1]heptane, and spiro[2,3]hexane. Cycloalkyl groups may be substituted or unsubstituted.
  • aryl is a functional group or substituent derived from an aromatic ring and encompasses monocyclic aromatic rings and bicyclic, tricyclic, and fused ring systems wherein at least one ring in the system is aromatic.
  • Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalenyl.
  • heteroaryl ring refers to an aromatic ring comprising at least one ring atom that is a heteroatom, such as O, N, or S.
  • Heteroaryl groups encompass monocyclic rings and bicyclic, tricyclic, bridged, fused, and spiro ring systems (including mono spiro and dispiro rings) wherein at least one ring in the system is aromatic.
  • Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and indoline.
  • heterocyclyl ring refers to a non-aromatic hydrocarbon containing 3 to 12 atoms in a ring (such as, for example, 3-10 atoms) comprising at least one ring atom that is a heteroatom, such as O, N, or S, and may include one or more unsaturated bonds.
  • heterocyclyl rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono spiro and di spiro rings.
  • Substituted indicates that at least one hydrogen of the “substituted” group is replaced by a substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at each position.
  • Non-limiting examples of protecting groups for nitrogen include, for example, t-butyl carbamate (Boc), benzyl (Bn), para-m ethoxybenzyl (PMB), tetrahydropyranyl (THP), 9- fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloe or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.
  • a comprehensive list of nitrogen protecting groups can be found in Wuts, P. G. M. “Greene’s Protective Groups in Organic Synthesis: Fifth Edition,”
  • deuterated derivative(s) refers to a compound having the same chemical structure as a reference compound, with one or more hydrogen atoms replaced by a deuterium atom.
  • the one or more hydrogens replaced by deuterium are part of an alkyl group.
  • the one or more hydrogens replaced by deuterium are part of a methyl group.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • CFTR modulator refers to a compound that increases the activity of CFTR.
  • the increase in activity resulting from a CFTR modulator includes, but is not limited to, compounds that correct, potentiate, stabilize, and/or amplify CFTR.
  • CFTR corrector or “corrector” refer to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface.
  • novel compounds disclosed herein are CFTR correctors. Tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, as referenced herein, are also CFTR correctors.
  • CFTR potentiator and “potentiator,” as used interchangeably herein, refer to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport. Ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl- 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and their deuterated derivatives and pharmaceutically acceptable salts are CFTR potentiators.
  • a description of a combination of compound selected from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing the combination will typically, but not necessarily, include a CFTR potentiator, such as, e.g., ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, or a deuterated derivative or pharmaceutically acceptable salt of any of the foregoing.
  • a CFTR potentiator such as, e.g., ivacaftor, deutivacaft
  • a combination of at least one compound selected from compounds of Formula I, compounds of any of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing will include a potentiator selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof and may also include another CFTR corrector, such as, e.g.
  • a reference to “Compounds 1 - 508” in this disclosure is intended to represent a reference to each of Compounds 1 through 508 individually or a reference to groups of compounds, such as, e.g., Compounds 1-474, Compounds 475-506, and Compounds 507 and 508.
  • the term “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refers to a biologically active compound.
  • the terms “patient” and “subject” are used interchangeably and refer to an animal, including a human.
  • an effective dose and “effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF).
  • the exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
  • the terms “treatment,” “treating,” and the like generally mean the improvement in one or more symptoms of CF or lessening the severity of CF or one or more symptoms of CF in a subject.
  • Treatment includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and/or liver function, reduction of chest infections, and/or reductions in coughing or shortness of breath. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.
  • the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other.
  • references herein to methods of treatment e.g., methods of treating a CFTR mediated disease or a method of treating cystic fibrosis using one or more compounds of the disclosure optionally in combination with one or more additional CFTR modulating agents (e.g., a compound chosen from compounds of Formula I, compounds of any of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulating agents) should also be interpreted as references to: - one or more compounds (e.g., a compound chosen from compounds of Formula I, compounds of any of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salt
  • references herein to methods of treatment e.g., methods of treating a CFTR mediated disease or a method of treating cystic fibrosis
  • a pharmaceutical composition of the disclosure e.g., a pharmaceutical composition comprising at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulating agents
  • a pharmaceutical composition e.g., a pharmaceutical composition comprising at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable
  • the terms “about” and “approximately” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values are measured or determined. In some embodiments, the terms “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.
  • the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of product >1 g/l).
  • the term “room temperature” or “ambient temperature” means 15 °C to 30 °C.
  • minimal function (MF) mutations refer to CFTR gene mutations associated with minimal CFTR function (little-to-no functioning CFTR protein) and include, for example, mutations associated with severe defects in ability of the CFTR channel to open and close, known as defective channel gating or “gating mutations”; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel conductance.
  • the term “pharmaceutically acceptable salt” refers to a salt form of a compound of this disclosure, wherein the salt is nontoxic.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • a “free base” form of a compound, for example, does not contain an ionically bonded salt.
  • the amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. It is noted that the disclosed amounts of the compounds or their pharmaceutically acceptable salts thereof herein are based upon their free base form.
  • Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Table 1 of that article provides the following pharmaceutically acceptable salts:
  • Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid
  • salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid
  • salts formed by using other methods used in the art such as ion exchange.
  • Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • any of the novel compounds disclosed herein such as, for example, compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can act as a CFTR modulator, i.e., it modulates CFTR activity in the body.
  • a CFTR mutation may affect the CFTR quantity, i.e., the number of CFTR channels at the cell surface, or it may impact CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations affecting CFTR quantity include mutations that cause defective synthesis (Class I defect), mutations that cause defective processing and trafficking (Class II defect), mutations that cause reduced synthesis of CFTR (Class V defect), and mutations that reduce the surface stability of CFTR (Class VI defect). Mutations that affect CFTR function include mutations that cause defective gating (Class III defect) and mutations that cause defective conductance (Class IV defect). Some CFTR mutations exhibit characteristics of multiple classes. Certain mutations in the CFTR gene result in cystic fibrosis.
  • the disclosure provides methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of any of the novel compounds disclosed herein, such as for example, compounds of Formula I, compounds of Formulae la, Ila, lib, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient, such as one or more CFTR modulating agents.
  • compounds of Formula I compounds of Formulae la, Ila, lib, III, IV, V, and VI
  • Compounds 1 - 508 tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient, such as one or more CFTR modulating agents.
  • the one or more CFTR modulating agents are selected from ivacaftor, deutivacaftor, lumacaftor, and tezacaftor.
  • the patient has an F508del/minimal function (MF) genotype, F508del/F508del genotype (homozygous for the F508del mutation), F508del/gating genotype, or F508del/residual function (RF) genotype.
  • MF F508del/minimal function
  • F508del/F508del genotype homozygous for the F508del mutation
  • F508del/gating genotype F508del/gating genotype
  • F508del/residual function (RF) genotype F508del/residual function
  • the patient is heterozygous and has one F508del mutation.
  • the patient is homozygous for the N1303K mutation
  • 5 mg to 500 mg of a compound disclosed herein, a tautomer thereof, a deuterated derivatives of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing are administered daily.
  • the patient has at least one F508del mutation in the CFTR gene.
  • the patient has a CFTR gene mutation that is responsive to a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure based on in vitro data.
  • the patient is heterozygous and has an F508del mutation on one allele and a mutation on the other allele selected from Table 2: Table 2: CFTR Mutations
  • the disclosure also is directed to methods of treatment using isotope-labelled compounds of the afore-mentioned compounds, or pharmaceutically acceptable salts thereof, wherein the formula and variables of such compounds and salts are each and independently as described above or any other embodiments described above, provided that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled).
  • isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • the isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and/or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H)- and/or carbon-14 ( 14 C)-labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.
  • deuterium ( 2 H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non- 2 H-labelled compounds.
  • deuterium ( 2 H)-labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which could be desired.
  • the isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)- labelled ones. In some embodiments, the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium. In chemical structures, deuterium is represented as “D.”
  • deuterium is represented as “D.”
  • the concentration of the isotope(s) (e.g., deuterium) incorporated into the isotope-labelled compounds and salts of the disclosure may be defined by the isotopic enrichment factor.
  • the term “isotopic enrichment factor,” as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of the disclosure is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • One aspect disclosed herein provides methods of treating cystic fibrosis and other CFTR mediated diseases using any of the novel compounds disclosed herein, such as, for example, compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.
  • at least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, and anti-inflammatory agents.
  • the additional therapeutic agent is an antibiotic.
  • antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.
  • the additional agent is a mucolyte.
  • Exemplary mucolytes useful herein includes Pulmozyme®.
  • the additional agent is a bronchodilator.
  • bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.
  • the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs.
  • agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.
  • the additional agent is a nutritional agent.
  • Exemplary nutritional agents include pancrelipase (pancreatic enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation.
  • the additional nutritional agent is pancrelipase.
  • at least one additional active pharmaceutical ingredient is selected from CFTR modulating agents.
  • the at least one additional active pharmaceutical ingredient is selected from CFTR potentiators.
  • the potentiator is selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • the at least one additional active pharmaceutical ingredient is chosen from CFTR correctors.
  • the correctors are selected from lumacaftor, tezacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • the at least one additional active pharmaceutical ingredient is chosen from (a) tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and/or (b) ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • the combination therapies provided herein comprise (a) a compound selected from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; or (c) at least one compound selected from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • the combination therapies provided herein comprise (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) at least one compound selected from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • the combination therapies provided herein comprise (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and/or (c) at least one compound selected from (6R,12R)-17-amino-12- methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca- 1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from ivacaftor and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from deutivacaftor and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from (6R,12R)-17- amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from (6R,12R)-17- amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, llb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, llb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, llb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, llb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, llb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, llb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae la, Ila, llb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof, are administered once daily and at least one compound chosen from ivacaftor and pharmaceutically acceptable salts thereof, are administered twice daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from lumacaftor and pharmaceutically acceptable salts thereof, are administered once daily and at least one compound chosen from ivacaftor and pharmaceutically acceptable salts thereof, are administered twice daily.
  • Compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, tezacaftor, ivacaftor, and deutivacaftor, and their pharmaceutically acceptable salts and deuterated derivatives thereof can be administered in a single pharmaceutical composition or separate pharmaceutical compositions. Such pharmaceutical compositions can be administered once daily or multiple times daily, such as twice daily.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • At least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; and at least one compound chosen from tezacaftor and deuterated and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered in a second pharmaceutical composition.
  • the second pharmaceutical composition comprises a half of a daily dose of ivacaftor and the other half of the daily dose of ivacaftor is administered in a third pharmaceutical composition.
  • at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in a first pharmaceutical composition; and at least one compound chosen from lumacaftor and deuterated and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered in a second pharmaceutical composition.
  • the second pharmaceutical composition comprises a half of a daily dose of ivacaftor and the other half dose of ivacaftor is administered in a third pharmaceutical composition.
  • at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in a first pharmaceutical composition; and at least one compound chosen from tezacaftor, lumacaftor and deuterated and pharmaceutically acceptable salts thereof and at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol
  • the first pharmaceutical composition is administered to the patient twice daily. In some embodiments, the first pharmaceutical composition is administered once daily. In some embodiments, the first pharmaceutical composition is administered once daily and, when the first pharmaceutical composition comprises ivacaftor, a second composition comprising only ivacaftor is administered once daily.
  • Any suitable pharmaceutical compositions can be used for compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • Some exemplary pharmaceutical compositions for tezacaftor and its pharmaceutically acceptable salts can be found in WO 2011/119984 and WO 2014/014841, incorporated herein by reference.
  • Some exemplary pharmaceutical compositions for ivacaftor and its pharmaceutically acceptable salts can be found in WO 2007/134279, WO 2010/019239, WO 2011/019413, WO 2012/027731, and WO 2013/130669, and some exemplary pharmaceutical compositions for deutivacaftor and its pharmaceutically acceptable salts can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017/053455, and WO 2018/080591, all of which are incorporated herein by reference.
  • compositions for lumacaftor and its pharmaceutically acceptable salts can be found in WO 2010/037066, WO 2011/127421, and WO 2014/071122, incorporated herein by reference.
  • Pharmaceutical Compositions [00107] Another aspect of the disclosure provides a pharmaceutical composition comprising at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier.
  • the disclosure provides pharmaceutical compositions comprising at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.
  • the at least one additional active pharmaceutical ingredient is a CFTR modulator.
  • the at least one additional active pharmaceutical ingredient is a CFTR corrector.
  • the at least one additional active pharmaceutical ingredient is a CFTR potentiator.
  • the pharmaceutical composition comprises at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1 - 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
  • Any pharmaceutical composition disclosed herein may comprise at least one pharmaceutically acceptable carrier.
  • the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants.
  • the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.
  • compositions described herein are useful for treating cystic fibrosis and other CFTR mediated diseases.
  • compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier.
  • the at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles.
  • the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • Remington The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J.
  • Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, ge
  • a compound of Formula I a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; Ring B is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; V is selected from O and NH; W 1 is selected from N and CH; W 2 is selected from N and CH, provided that at least one of W 1 and W 2 is N; Z is selected from O, NR ZN , and C(R ZC ) 2 ,
  • each R 3 is independently selected from C 1 -C 6 alkyl.
  • R YN is selected from: ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o cyano, o N(R N ) 2 , o C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , and ⁇ C 6 -C 10 aryl, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C 6 -C 10 aryl, and N(R N ) 2 , o C 3 -C 10 cycloalkyl, and o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , o C 1 -C 10 cycloalkyl, and o 5- to 10-membere
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 fluoroalkyl, and ⁇ C 3 -C 10 cycloalkyl. 21.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o NH 2 , o NHCOMe, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, and o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, and ⁇ C 6 -C 10 aryl, and or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1- 3 groups selected from: ⁇ cyano, ⁇ C 1 -C 6 alkyl, and ⁇ C 1 -C 6 alkoxy
  • a compound of Formula Ia a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, Ring B, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are defined as according to embodiment 1, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,
  • 33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 22 to 32, wherein each R 3 is independently selected from C 1 -C 6 alkyl. 34.
  • each R 5 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, and C 6 -C 10 aryl.
  • R YN is selected from: ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o cyano, o N(R N ) 2 , o C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , and ⁇ C 6 -C 10 aryl, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C 6 -C 10 aryl, and N(R N ) 2 , o C 3 -C 10 cycloalkyl, and o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 fluoroalkyl, and ⁇ C 3 -C 10 cycloalkyl. 41.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o NH 2 , o NHCOMe, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, and o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, and ⁇ C 6 -C 10 aryl, and or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1- 3 groups selected from: ⁇ cyano, ⁇ C 1 -C 6 alkyl, and ⁇ C 1 -C 6 alk
  • a compound of Formula IIa a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are defined as according to embodiment 1, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2-
  • each R 5 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, and C 6 -C 10 aryl. 56.
  • R YN is selected from: ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o cyano, o N(R N ) 2 , o C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , and ⁇ C 6 -C 10 aryl, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C 6 -C 10 aryl, and N(R N ) 2 , o C 3 -C 10 cycloalkyl, and o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 fluoroalkyl, and ⁇ C 3 -C 10 cycloalkyl. 58.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o NH 2 , o NHCOMe, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, and o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, and ⁇ C 6 -C 10 aryl, or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1- 3 groups selected from: ⁇ cyano, ⁇ C 1 -C 6 alkyl, and ⁇ C 1 -C 6 alk
  • a compound of Formula IIb a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are defined as according to embodiment 1, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,
  • 66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 59 to 65, wherein two R ZC are taken together to form an oxo group. 67.
  • each R 3 is independently selected from C 1 -C 6 alkyl. 68.
  • R YN is selected from: ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o cyano, o N(R N ) 2 , o C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , and ⁇ C 6 -C 10 aryl, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C 6 -C 10 aryl, and N(R N ) 2 , o C 3 -C 10 cycloalkyl, and o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 fluoroalkyl, and ⁇ C 3 -C 10 cycloalkyl. 75.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o NH 2 , o NHCOMe, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, and o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 6 -C 10 aryl, and or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1- 3 groups selected from: ⁇ cyano, ⁇ C 1 -C 6 alkyl, and ⁇ C 1 -C 6 al
  • a compound of Formula III a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein W 1 , W 2 , Z, L 1 , L 2 , R 4 , R 5 , and R YN are defined as according to embodiment 1, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2- tetradeutero)
  • R YN is selected from: ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o cyano, o N(R N ) 2 , o C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , and ⁇ C 6 -C 10 aryl, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C 6 -C 10 aryl, and N(R N ) 2 , o C 3 -C 10 cycloalkyl, and o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 fluoroalkyl, and ⁇ C 3 -C 10 cycloalkyl.
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 flu
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o NH 2 , o NHCOMe, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, and o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, and ⁇ C 6 -C 10 aryl, and or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1- 3 groups selected from: ⁇ cyano, ⁇ C 1 -C 6 alkyl, and ⁇ C 1 -C 6 al
  • a compound of Formula IV a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z, L 1 , L 2 , R 4 , R 5 , and R YN are defined as according to embodiment 1, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2- tetradeutero)spiro[2.3]hex
  • each R 5 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, and C 6 -C 10 aryl. 93.
  • R YN is selected from: ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o cyano, o N(R N ) 2 , o C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , and ⁇ C 6 -C 10 aryl, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C 6 -C 10 aryl, and N(R N ) 2 , o C 3 -C 10 cycloalkyl, and o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 fluoroalkyl, and ⁇ C 3 -C 10 cycloalkyl.
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 flu
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o NH 2 , o NHCOMe, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, and o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 6 -C 10 aryl, and or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1- 3 groups selected from: ⁇ cyano, ⁇ C 1 -C 6 alkyl, and ⁇ C 1 -C 6 al
  • a compound of Formula V a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z, L 1 , L 2 , R 4 , R 5 , and R YN are defined as according to embodiment 1, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2- tetradeutero)spiro[2.3]hex
  • each R 5 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, and C 6 -C 10 aryl. 102.
  • R YN is selected from: ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o cyano, o N(R N ) 2 , o C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , and ⁇ C 6 -C 10 aryl, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C 6 -C 10 aryl, and N(R N ) 2 , o C 3 -C 10 cycloalkyl, o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 fluoroalkyl, and ⁇ C 3 -C 10 cycloalkyl. 104.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o NH 2 , o NHCOMe, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, and o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, and ⁇ C 6 -C 10 aryl, or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1- 3 groups selected from: ⁇ cyano, ⁇ C 1 -C 6 alkyl, and ⁇ C 1 -C 6 al
  • a compound of Formula VI a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 1 , R 4 , R 5 , and R YN are defined as according to embodiment 1, with the proviso that the compound is not selected from: (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione, (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[(1,1,2,2- tetradeutero)spiro[2.3]hexan-5-yl]
  • R YN is selected from: ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o cyano, o N(R N ) 2 , o C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N(R N ) 2 , and ⁇ C 6 -C 10 aryl, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen, oxo, C 6 -C 10 aryl, and N(R N ) 2 , o C 3 -C 10 cycloalkyl, o 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from: ⁇ hydroxyl, ⁇ oxo, ⁇ N
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 fluoroalkyl, and ⁇ C 3 -C 10 cycloalkyl.
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ N(R N ) 2 , provided that two N(R N ) 2 are not bonded to the same carbon, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, and o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 flu
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o NH 2 , o NHCOMe, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, and o 3- to 14-membered heterocyclyl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, and ⁇ C 6 -C 10 aryl, or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a 3- to 10-membered heterocyclyl optionally substituted with 1- 3 groups selected from: ⁇ cyano, ⁇ C 1 -C 6 alkyl, and ⁇ C 1 -C 6 alk
  • a pharmaceutical composition comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 113, and a pharmaceutically acceptable carrier.
  • composition of embodiment 114 further comprising one or more additional therapeutic agents.
  • composition of embodiment 115, wherein the one or more additional therapeutic agents is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, and anti-inflammatory agents.
  • the one or more additional therapeutic agent is an antibiotic selected from tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.
  • TIP tobramycin inhaled powder
  • aztreonam including the aerosolized form of aztreonam
  • amikacin including liposomal formulations thereof
  • ciprofloxacin including formulations thereof suitable for administration by inhalation
  • levoflaxacin including aerosolized formulations thereof
  • combinations of two antibiotics e.g., fosfomycin and tobramycin.
  • composition of embodiment 118, wherein the one or more CFTR modulating agents are selected from CFTR correctors.
  • composition of embodiment 118, wherein the one or more CFTR modulating agents comprises at least one CFTR potentiator and at least one CFTR corrector.
  • CFTR modulating agents are selected from (a) tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (b) ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. 123.
  • the one or more CFTR modulating agents are selected from (a) tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; or (b) (6R,12R)-17- amino- 12-methyl-6, 15-bis(trifluoromethyl)- 13,19-dioxa-3 ,4,18- triazatricyclo[12.3.1
  • composition of any one of embodiments 118 to 121, wherein the composition comprises tezacaftor and ivacaftor.
  • composition of any one of embodiments 118 to 121, wherein the composition comprises tezacaftor and deutivacaftor.
  • composition of any one of embodiments 118 to 121, wherein the composition comprises tezacaftor and (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13, 19-dioxa-3,4, 18-triazatricyclo[12.3.1.12,5] nonadeca- 1 ( 18), 2, 4, 14, 16-pentaen-6-ol .
  • composition of any one of embodiments 118 to 121, wherein the composition comprises lumacaftor and ivacaftor.
  • composition of any one of embodiments 118 to 121, wherein the composition comprises lumacaftor and deutivacaftor.
  • composition of any one of embodiments 118 to 121, wherein the composition comprises lumacaftor and (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13, 19-dioxa-3,4, 18-triazatricyclo[12.3.1.12,5] nonadeca- 1 ( 18), 2, 4, 14, 16-pentaen-6-ol .
  • a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 113, or a pharmaceutical composition according to any one of embodiments 114 to 129.
  • the method of embodiment 130 further comprising administering to the patient one or more additional therapeutic agents prior to, concurrent with, or subsequent to the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 113, or the pharmaceutical composition according to embodiment 114.
  • the one or more additional therapeutic agents is(are) selected from CFTR modulating agents.
  • the one or more CFTR modulating agents are selected from CFTR potentiators.
  • 134 The method of embodiment 132, wherein the one or more CFTR modulating agents are selected from CFTR correctors. 135.
  • the one or more CFTR modulating agents comprise both a CFTR potentiator and an additional CFTR corrector.
  • the CFTR potentiator is selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19- dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • the CFTR potentiator is selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19- dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6
  • CFTR corrector is selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • the one or more additional therapeutic agent(s) is a compound selected from tezacaftor, ivacaftor, deutivacaftor, lumacaftor, and pharmaceutically acceptable salts thereof.
  • the one or more additional therapeutic agent(s) is a compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • the one or more additional therapeutic agents are tezacaftor and ivacaftor.
  • the one or more additional therapeutic agents are tezacaftor and deutivacaftor. 142.
  • the method of embodiment 131, wherein the one or more additional therapeutic agents are tezacaftor and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol. 143.
  • the method of embodiment 131, wherein the one or more additional therapeutic agents are lumacaftor and ivacaftor.
  • the one or more additional therapeutic agents are lumacaftor and deutivacaftor. 145.
  • 149. A deuterated derivative of a compound selected from Compounds 1-508.
  • 150. A pharmaceutically acceptable salt of a compound selected from Compounds 1-508.
  • a pharmaceutical composition comprising a compound selected from Compounds 1-508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a deuterated derivative of a compound selected from Compounds 1-508 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from Compounds 1-508 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound selected from Compounds 1-508 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-508; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-508; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-508; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier. 162.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-508; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier. 163.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; (c) a CRTR potentiator; and (d) a pharmaceutically acceptable carrier. 165.
  • a pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-508; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-508; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier. 168.
  • a pharmaceutical composition comprising a compound selected from Compounds 1-508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing and a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis. 173.
  • a pharmaceutical composition comprising a deuterated derivative of a compound selected from Compounds 1-508 and a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from Compounds 1-508 and a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis. 175.
  • a pharmaceutical composition comprising a compound selected from Compounds 1-508 and a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical comprising (a) a deuterated derivative of a compound selected from Compounds 1-508; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-508; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier. 180.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis. 181.
  • a pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-508; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis. 182.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-508; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; (c) a CRTR potentiator; and (d) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-508; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis. 186.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-508; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 508; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • NMR (1D & 2D) spectra were also recorded on a Bruker AVNEO 400 MHz spectrometer operating at 400 MHz and 100 MHz respectively equipped with a 5 mm multinuclear Iprobe.
  • NMR spectra were also recorded on a Varian Mercury NMR instrument at 300 MHz for 1 H using a 45 degree pulse angle, a spectral width of 4800 Hz and 28860 points of acquisition. FID were zero-filled to 32k points and a line broadening of 0.3Hz was applied before Fourier transform.
  • 19 F NMR spectra were recorded at 282 MHz using a 30 degree pulse angle, a spectral width of 100 kHz and 59202 points were acquired.
  • FID were zero-filled to 64k points and a line broadening of 0.5 Hz was applied before Fourier transform.
  • NMR spectra were also recorded on a Bruker Avance III HD NMR instrument at 400 MHz for 1 H using a 30 degree pulse angle, a spectral width of 8000 Hz and 128k points of acquisition. FID were zero-filled to 256k points and a line broadening of 0.3Hz was applied before Fourier transform.19F NMR spectra were recorded at 377 MHz using a 30 deg pulse angle, a spectral width of 89286 Hz and 128k points were acquired. FID were zero-filled to 256k points and a line broadening of 0.3 Hz was applied before Fourier transform.
  • NMR spectra were also recorded on a Bruker AC 250MHz instrument equipped with a: 5mm QNP(H1/C13/F19/P31) probe (type: 250-SB, s#23055/0020) or on a Varian 500MHz instrument equipped with a ID PFG, 5 mm, 50-202/500 MHz probe (model/part# 99337300).
  • Final purity of compounds was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 3.0 minutes.
  • Mobile phase A H 2 O (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • Final purity was calculated by averaging the area under the curve (AUC) of two UV traces (220 nm, 254 nm).
  • AUC area under the curve
  • Low-resolution mass spectra were reported as [M+1] + species obtained using a single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source capable of achieving a mass accuracy of 0.1 Da and a minimum resolution of 1000 (no units on resolution) across the detection range.
  • ESI electrospray ionization
  • Optical purity of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate was determined using chiral gas chromatography (GC) analysis on an Agilent 7890A/MSD 5975C instrument, using a Restek Rt- ⁇ DEXcst (30 m x 0.25 mm x 0.25 ⁇ m_df) column, with a 2.0 mL/min flow rate (H 2 carrier gas), at an injection temperature of 220 °C and an oven temperature of 120 °C, 15 minutes.
  • GC chiral gas chromatography
  • LC method A Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 3.0 minutes.
  • Mobile phase A H 2 O (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • LC method D Acquity UPLC BEH C 18 column (30 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minute.
  • Mobile phase A H 2 O (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • LC method I Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn:186002350), and a dual gradient run from 1-99% mobile phase B over 5.0 minutes.
  • Mobile phase A H 2 O (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • LC method J Reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes.
  • Mobile phase A H 2 O (0.05 % NH4HCO 2 ).
  • Mobile phase B CH 3 CN.
  • LC method K Kinetex Polar C 18 3.0 x 50 mm 2.6 ⁇ m, 3 min, 5-95% ACN in H 2 O (0.1% Formic Acid) 1.2 mL/min.
  • LC method Q Reversed phase UPLC using an Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 30- 99% mobile phase B over 2.9 minutes.
  • Mobile phase A H 2 O (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • LC method S Merckmillipore Chromolith SpeedROD C 18 column (50 x 4.6 mm) and a dual gradient run from 5 - 100% mobile phase B over 12 minutes.
  • Mobile phase A water (0.1 % CF 3 CO 2 H).
  • Mobile phase B acetonitrile (0.1 % CF 3 CO 2 H).
  • LC method T Merckmillipore Chromolith SpeedROD C 18 column (50 x 4.6 mm) and a dual gradient run from 5 - 100% mobile phase B over 6 minutes.
  • Mobile phase A water (0.1 % CF 3 CO 2 H).
  • Mobile phase B acetonitrile (0.1 % CF 3 CO 2 H).
  • LC method U Kinetex Polar C 18 3.0 x 50 mm 2.6 ⁇ m, 6 min, 5-95% ACN in H 2 O (0.1% Formic Acid) 1.2 mL/min.
  • LC method V Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-30% mobile phase B over 2.9 minutes.
  • Mobile phase A H 2 0 (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • LC method W water Cortex 2.7 ⁇ C 18 (3.0 mm x 50 mm), Temp: 55 °C; Flow: 1.2 mL/min; mobile phase: 100% water with 0.1% trifluoroacetic(TFA) acid then 100% acetonitrile with 0.1% TFA acid, grad:5% to 100% B over 4 min, with stay at 100% B for 0.5min, equilibration to 5% B over 1.5 min.
  • LC method X UPLC Luna C 18 (2) 50 x 3mm 3 ⁇ m. run: 2.5 min.
  • LC method 1A Reversed phase UPC2 using a Viridis BEH 2-Ethylpyridine column (150 ⁇ 2.1 mm, 3.5 ⁇ m particle) made by Waters (pn: 186006655), and a dual gradient run from 5-80% mobile phase B over 4.5 minutes.
  • Mobile phase A CO 2 .
  • Mobile phase B MeOH (20 mM NH 3 ).
  • Step 2 tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6- dimethylphenyl)pyrimidin-2-yl]carbamate. [00143] All solvents were degassed prior to use.
  • the reaction was cooled to ambient temperature and diluted with water (704 mL).
  • the aqueous phase was separated and extracted with EtOAc (704 mL).
  • the organic phase was washed with 700 mL of brine, dried over magnesium sulfate, filtered and concentrated in vacuo.
  • the crude product was chromatographed on a 1500 g silica gel column eluting with 0-30% EtOAc/hexanes.
  • the product fractions (eluted at 15% EtOAc) were combined and concentrated in vacuo affording the product as a clear oil which crystallized on standing.
  • Step 3 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt)
  • tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl) pyrimidin-2- yl]carbamate 514.8 g, 915.9 mmol
  • dichloromethane 4 L
  • Hydrogen chloride in p-dioxane (1 L, 4 mol) was added and the mixture was stirred overnight at room temperature.
  • Step 4 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine
  • 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt) (166 g, 614.5 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt) (30 g, 111.0 mmol) were suspended in DCM (2.5 L), treated with NaOH (725 mL of 1 M, 725.0 mmol) and stirred at room temperature for 1 hour. The mixture was transferred into a separatory funnel and left standing over night.
  • the DCM phase was separated and the aqueous phase with insoluble material was extracted twice more with DCM (2 x 500mL).
  • the combined brown DCM phases were stirred over magnesium sulfate and charcoal for 1 hour, filtered and the yellow solution concentrated to a volume of ⁇ 500 mL.
  • the solution was diluted with heptane (750 mL) and DCM was removed under reduced pressure at 60 °C to give a cream suspension. It was stirred at room temperature for 1 hour, filtered, washed with cold heptane and dried to give 4-chloro-6- (2,6-dimethylphenyl)pyrimidin-2-amine (157 g, 91%) as a cream solid.
  • Step 5 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine 235 g, 985.5 mmol was dissolved in MeTHF (2.3 L) and cooled in an ice bath under stirring and nitrogen.
  • methyl 3-chlorosulfonylbenzoate (347 g, 1.479 mol) was added in one portion (seems slightly endothermic) and to the cold pale-yellow solution a solution of 2-methyl-butan-2-ol (Lithium salt) (875 mL of 3.1 M, 2.712 mol) (in heptane) was added dropwise over 1.25 hour (exothermic, internal temperature from 0 to 10 °C). The ice bath was removed and the greenish solution was stirred for 4 hours at room temperature.
  • 2-methyl-butan-2-ol Lithium salt
  • the phases were separated and the NaOH phase was washed twice with MeTHF (2 x 500 mL) and the combined organic phases were extracted once with 2M NaOH (1 x 250 mL).
  • the combined NaOH phases were combined, stirred in an ice bath and slowly acidified by addition of HCl (416 mL of 36 %w/w, 4.929 mol) while keeping the internal temperature between 10 and 20 °C.
  • HCl 416 mL of 36 %w/w, 4.929 mol
  • the final pH was adjusted to 2-3 by addition of solid citric acid.
  • the formed yellow tacky suspension was stirred at room temperature overnight to give a cream crisp suspension.
  • the solid was collected by filtration, washed with plenty of water and sucked dry for 3 hours.
  • Example B Preparation of 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)-4-methyl-pentoxy]-6- (2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • (2R)-2-amino-4-methyl-pentan-1-ol (12.419 g, 105.97 mmol) in anhydrous THF (200 mL) at room temperature under nitrogen was added sodium tert- butoxide (15.276 g, 158.95 mmol).
  • reaction mixture was stirred for 10 minutes and 3-[[4- chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (22.14 g, 52.983 mmol) was added.
  • the reaction mixture was placed on a water bath preheated to 60 °C and stirred for 20 minutes. After cooling to room temperature, di-tert-butyl dicarbonate (69.381 g, 317.90 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (150 mL).
  • the obtained white solid was re-purified by silica gel chromatography using 0-40% acetone (0.15% acetic acid buffer) gradient in hexanes (0.15% acetic acid buffer) to afford 3-[[4- [(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (20.73 g, 61%) as a white solid.
  • ESI-MS m/z calc.598.2461, found 599.4 (M+1) + ; Retention time: 5.85 minutes (LC Method S).
  • Step 2 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt).
  • Step 2 3-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00150] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (20 g, 47.862 mmol) was suspended in a mixture of 2-methyltetrahydrofuran (80 mL) and DMF (20 mL) and the solution was cooled to -5 °C.
  • Example D Preparation of 3-[[4-[(2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6- (2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 4,4,4-Trifluoro-3,3-dimethyl-butanal
  • a 1 L three-neck flask was charged with 4,4,4-trifluoro-3,3-dimethyl-butan-1-ol (8.987 g, 57.555 mmol), DCM (63 mL), water (63 mL), NaBr (544 mg, 5.2870 mmol), sodium bicarbonate (12.32 g, 146.66 mmol) and TEMPO (92 mg, 0.5888 mmol).
  • Step 3 (2R)-5,5,5-Trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanamide and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanamide [00153] To a solution of a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanenitrile (14.87 g, 52.300 mmol) in DCM (105 mL) was added sulfuric acid (56.3 g, 551.06 mmol).
  • Step 4 (2R)-5,5,5-Trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid
  • (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanamide 11.35 g, 37.541 mmol
  • HOAc 50 mL
  • conc. HCl 65 mL of 11.8 M, 767.00 mmol
  • water 50 mL
  • HCl 40 mL of 11.8 M, 472.00 mmol
  • HOAc 10 mL
  • the mixture was stirred at 100 °C overnight. More HCl in water (20 mL of 6 M, 120.00 mmol) was added. After 7 h at 100 °C, more HCl in water (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C overnight. It became a clear solution. More HCl in water (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C for 7 h, more HCl in water (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C overnight.
  • Step 5 (2R)-5,5,5-Trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentan-1-ol [00155] To a suspension of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanoic acid (hydrochloride salt) (13.04 g, 36.267 mmol) in THF (200 mL) at 35 °C was added LAH in THF (100 mL of 1 M, 100.00 mmol) dropwise.
  • Step 6 (2R)-2-Amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol
  • (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentan-1-ol (hydrochloride salt) 11.56 g, 35.482 mmol
  • EtOH 200 mL
  • 10% palladium on carbon 50% wet (5 g, 2.3492 mmol).
  • the mixture was hydrogenated in a Parr shaker hydrogenation apparatus at 40 psi of hydrogen at rt for 9 h.
  • Step 7 3-[[4-[(2R)-2-Amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00157] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (6.12 g, 14.65 mmol) and (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (3.27 g, 14.75 mmol) were combined in THF (30 mL) and the resulting suspension was cooled in a water-ice bath.
  • the organic phase was carefully treated with a saturated aqueous solution of sodium carbonate (500ml, strong gas evolution, pH ⁇ 10 at the end).
  • the three-phase mixture was stirred at room temperature for 1 h and the solid was removed by filtration (large glass frit).
  • the phases (yellow cloudy Diethylether phase, colorless water phase) were separated and the organic phase was washed once more with a saturated aqueous solution of sodium carbonate (250 mL), once with 1M sodium thiosulfate (250 mL) and once with brine (250 mL).
  • Step 3 2-[[(1R)-1-Phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propanenitrile [00160] 2-[1-(Trifluoromethyl)cyclopropyl]acetaldehyde (102 g, 670.5 mmol) in MeOH (700 mL) was treated with (1R)-1-phenylethanamine (86 mL, 667.1 mmol) and cooled in an ice bath.
  • Step 4 (2R)-2-[[(1R)-1-Phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propenamide [00161]
  • sulfuric acid (285 mL of 18 M, 5.130 mol) was added it was cooled in an ice bath.
  • the deep orange emulsion was carefully added to a mixture of ice and water (2.2 L) under mechanical stirring to give a yellow three phase mixture which was basified by slow addition of ammonium hydroxide (1.33 L of 30 %w/w, 10.25 mol) under ice cooling (very exothermic, internal temperature kept between 10 and 25 °C by adding ice).
  • the yellow emulsion was stirred for 10 minutes at room temperature (pH ⁇ 10), diluted with DCM (500 mL) and the phases were separated.
  • the aqueous phase was washed twice more with DCM (400 and 200 mL) and the combined organic phases were washed once with water/brine 1:1 (500 mL).
  • Step 5 (2R)-2-[[(1R)-1-Phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propanoic acid [00162]
  • (2R)-2-[[(1R)-1-phenylethyl]amino]- 3-[1-(trifluoromethyl)cyclopropyl]propanamide (hydrochloride salt) 147 g, 436.5 mmol
  • acetic acid 735 mL
  • HCl 1.3 L of 12 M, 15.60 mol
  • the colorless suspension was carefully heated to 60-65 °C (strong foaming, acetic acid (145 mL) was added) and the suspension was stirred at 60-65 °C for 16 h.
  • the suspension was then slowly heated to 100 °C (over 4 h, strong foaming) and the resulting solution was stirred at 100 °C for another 20 h.
  • the pale-yellow solution was concentrated under reduced pressure at 65 °C to a semisolid mass and it was treated with water (1.5 L).
  • the thick suspension was heated to 70-80 °C and left to cool to room temperature under stirring for 2 h. The solid was collected by filtration, washed with water and sucked dry overnight.
  • Step 6 (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propan-1-ol [00163]
  • (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (hydrochloride salt) (135 g, 399.7 mmol) was suspended in THF (2 L) (thick suspension).
  • the grey suspension was cooled in an ice bath and quenched by careful addition of water (44 mL, 2.442 mol), NaOH (41 mL of 6 M, 246.0 mmol) and water (44 mL, 2.442 mol) (high exotherm with first water addition, kept between 5 °C and 30 °C by cooling).
  • the grey suspension was heated to 50-55 ° C for 1 h, by which time a colorless suspension was obtained.
  • the warm suspension was filtered over a pad of Celite covered over magnesium sulfate.
  • Step 7 (2R)-2-Amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol
  • (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride salt) (63.3 g, 195.5 mmol) was dissolved in EtOH (630 mL) (under warming), and it was treated with Pd/C (6.3 g of 10 %w/w, 5.920 mmol) (12.5g of 50% water wet) and the reaction was stirred under 2 bar of hydrogen at 40 °C for 24 h.
  • Step 8 3-[[4-[(2R)-2-Amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00165] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (19.09 g, 45.68 mmol) and (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride salt) (10.18 g, 46.35 mmol) were dissolved in THF (100 mL) and cooled in an ice water bath.
  • Example F Preparation of (2R)-4-methyl-2-(spiro[2.3]hexan-5-ylamino)pentan-1-ol
  • Step 1 (2R)-4-Methyl-2-(spiro[2.3]hexan-5-ylamino)pentan-1-ol
  • a mixture of spiro [2.3]hexan-5-one (100 g, 1.040 mol) and (2R)-2-amino-4-methyl- pentan-1-ol (123.5 g, 1.054 mol) in DCE (1.5 L) was stirred at ambient temperature for 1 h.
  • To the mixture was added sodium triacetoxyborohydride (228 g, 1.076 mol) portionwise.
  • the mixture was stirred at ambient temperature for 18 h.
  • the reaction mixture was diluted with HCl (1.1 L of 2 M, 2.200 mol) until pH was ⁇ 1.
  • the aqueous phase was separated, and the organic phase extracted with HCl (600 mL of 2 M, 1.200 mol).
  • the organic phase (DCE) was separated and the aqueous layer was basified with NaOH (550 g of 50 %w/w, 6.875 mol) affording a solution at ⁇ pH 12.
  • the mixture was extracted 2X with EtOAc (1 L) and the combined organic phases were washed with brine (150 mL), dried over MgSO 4 , filtered and concentrated in vacuo affording a clear oil. Used without further purification.
  • Example G Preparation of 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol Step 1: 2-[1-(Trifluoromethyl)cyclopropyl]ethyl methanesulfonate [00168] A 1000 mL, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, a J-Kem temperature probe, an addition funnel and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 2-[1-(trifluoromethyl)cyclopropyl]ethanol (125 g, 811.0 mmol) and 2-methyltetrahydrofuran (625 mL) which provided a clear colorless solution.
  • 2-[1-(trifluoromethyl)cyclopropyl]ethanol 125 g, 811.0 mmol
  • 2-methyltetrahydrofuran 625 mL
  • the vessel was charged under a nitrogen atmosphere with 2-[1- (trifluoromethyl)cyclopropyl]ethyl methanesulfonate (50 g, 215.3 mmol) and dimethyl sulfoxide (250 mL) which provided a clear pale yellow solution. Stirring was commenced and the pot temperature was recorded at 19 °C.
  • the vessel was charged with sodium cyanide (13.19 g, 269.1 mmol), added as a solid in one portion. The mixture was heated to a pot temperature of 70 °C and the condition was maintained for 24 h. Upon heating all of the sodium cyanide dissolved and the reaction mixture turned to a light amber suspension.
  • the vessel was subsequently charged under a nitrogen atmosphere with 3-[1- (trifluoromethyl)cyclopropyl]propanenitrile (25 g, 153.2 mmol) and ethyl alcohol (375 mL) which provided a clear amber solution. Stirring was commenced and the pot temperature was recorded at 19 °C. The vessel was then charged with sodium hydroxide (102.1 mL of 6 M, 612.6 mmol), added in one portion. The resulting clear amber solution was heated to a pot temperature of 70 °C and the condition was maintained for 24 h. After cooling to room temperature, the reaction mixture was concentrated to remove the ethyl alcohol.
  • the residual aqueous was diluted with water (150 mL) and then transferred to a separatory funnel and partitioned with methyl tert- butyl ether (50 mL). The aqueous was removed and the pH was adjusted to pH ⁇ 1 with 6 M hydrochloric acid solution. The resulting aqueous solution was transferred to a separatory funnel and partitioned with methyl tert-butyl ether (250 mL). The organic was removed and the residual aqueous was extracted with methyl tert-butyl ether (2 X 150 mL). The combined organic was dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel.
  • Step 4 3-[1-(Trifluoromethyl)cyclopropyl]propan-1-ol [00171]
  • a 1000 mL, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, a J-Kem temperature probe and a nitrogen inlet/outlet.
  • the vessel was charged under a nitrogen atmosphere with lithium aluminum hydride pellets (6.775 g, 178.5 mmol).
  • the vessel was then charged under a nitrogen atmosphere with tetrahydrofuran (250 mL). Stirring was commenced and the pot temperature was recorded at 20 °C.
  • the mixture was allowed to stir at room temperature for 0.5 h to allow the pellets to dissolve.
  • the pot temperature of the resulting grey suspension was recorded at 24 °C.
  • the cooling bath was then charged with crushed ice/water and the pot temperature was lowered to 0 °C.
  • the addition funnel was charged with a solution of 3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (25 g, 137.3 mmol) in tetrahydrofuran (75 mL, 3 mL/g) and the clear pale yellow solution was added dropwise over 1 h. After the addition was completed, the pot temperature of the resulting greyish-brown suspension was recorded at 5 °C. The mixture was allowed to slowly warm to room temperature and continue to stir at room temperature for 24 h.
  • the suspension was cooled to 0 °C with a crushed ice/water cooling bath and then quenched by the very slow dropwise addition of water (6.775 mL), followed by 15 wt% sodium hydroxide solution (6.775 mL) and then finally with water (20.32 mL).
  • the pot temperature of the resulting white suspension was recorded at 5 °C.
  • the suspension was continued to stir at ⁇ 5 °C for 30 min and then filtered through a glass frit Buchner funnel with a 20 mm layer of celite. The filter cake was displacement washed with tetrahydrofuran (2 X 150 mL) and then dried under vacuum for 15 min.
  • Example H Preparation of 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylic acid
  • Step 1 Methyl 6-benzylsulfanylpyridine-2-carboxylate
  • phenylmethanethiol 28.408 g, 26.800 mL, 228.72 mmol
  • NaH 11.200 g, 60 %w/w, 280.03 mmol
  • Step 2 Methyl 6-chlorosulfonylpyridine-2-carboxylate [00173] A solution of methyl 6-benzylsulfanylpyridine-2-carboxylate (121.62 g, 431.47 mmol) in DCM (950 mL) and DI water (300 mL) was cooled in a -1 - 0 °C ice bath and, with vigorous stirring, sulfuryl chloride (228.14 g, 140 mL, 1.6396 mol) was added dropwise while the temperature was maintained below 5 °C. After the addition, the organic phase was separated, washed with DI water (2 x 500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • Step 3 Methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylate [00174] A solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (16.63 g, 71.161 mmol) and methyl 6-chlorosulfonylpyridine-2-carboxylate (16.8 g, 71.294 mmol) dissolved in anhydrous THF (680 mL) was cooled to - 78 °C.
  • Lithium bis(trimethylsilyl)amide (143 mL of 1 M, 143.00 mmol) in solution in THF was added dropwise. The mixture was allowed to warm up to 0 °C slowly and then 1M aqueous HCl (146 mL) was added, followed by DI water (680 mL). The THF was evaporated and the aqueous phase was extracted with chloroform (3 x 250 mL). The combined organic layers were washed with saturated aqueous NaCl (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was recrystallized in 10 % Acetone in Hexanes (500 mL).
  • Step 4 6-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyridine-2- carboxylic acid [00175] To a solution of methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylate (15.79 g, 36.477 mmol) in THF (180 mL) was added aqueous sodium hydroxide (182 mL of 1 M, 182.00 mmol). The reaction was stirred at RT for 1h.
  • Example I Preparation of 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)- 2-pyridyl]sulfamoyl]benzoic acid
  • Step 1 4-Chloro-6-(2,6-dimethylphenyl)pyridin-2-amine
  • Toluene (425 mL) and EtOH (213 mL) was added an aqueous solution of Sodium carbonate (115 mL of 2 M, 230.00 mmol) and the reaction mixture was degassed with nitrogen gas for 45 min.
  • Step 2 Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-2-pyridyl]sulfamoyl]benzoate [00177] To a solution of 4-chloro-6-(2,6-dimethylphenyl)pyridin-2-amine (4.9 g, 20.635 mmol) and methyl 3-chlorosulfonylbenzoate (4.9 g, 20.046 mmol) in THF (200 mL) was added dropwise Lithium bis(trimethylsilyl)amide (45 mL of 1 M, 45.000 mmol) at -78 °C under nitrogen.
  • reaction mixture was stirred for 30 minutes at -78 °C; then warmed up to 0 °C and stirred for 2 hours at 0 °C.
  • the reaction was quenched with cold 1.0 M Hydrochloric acid (50 mL) and diluted with water (200 mL).
  • the mixture was extracted with ethyl acetate (2 x 400 mL). The organic layers were combined, washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated.
  • Step 3 3-[[4-chloro-6-(2,6-dimethylphenyl)-2-pyridyl]sulfamoyl]benzoic acid [00178] To a stirring solution of 3-[4-chloro-6-(2,6-dimethyl-phenyl)-pyridin-2-ylsulfamoyl]- benzoic acid methyl ester (5.3 g, 12.3 mmol) in a mixture of tetrahydrofuran (80 mL) and water (80 mL) at room temperature was added lithium hydroxide monohydrate (1.55 g, 36.9 mmol) and the reaction mixture was stirred at 45 C for 2 hours.
  • Step 4 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)-2- pyridyl]sulfamoyl]benzoic acid [00179] A 20 mL vial was charged with 3-[[4-chloro-6-(2,6-dimethylphenyl)-2- pyridyl]sulfamoyl]benzoic acid (300 mg, 0.7196 mmol), (2R)-2-amino-4-methyl-pentan-1-ol (110 mg, 0.9387 mmol) and anhydrous tetrahydrofuran (12 mL), in that order.
  • Example J Preparation of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]- (methoxymethyl)sulfamoyl]benzoate
  • Step 1 Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]- (methoxymethyl)sulfamoyl]benzoate
  • Example K Preparation of 3-[[4-(2-amino-4,4,4-trifluoro-butoxy)-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 3-[[4-[2-(tert-Butoxycarbonylamino)-4,4,4-trifluoro-butoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 2 3-[[4-(2-Amino-4,4,4-trifluoro-butoxy)-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid [00182] A solution of 3-[[4-[2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (83 mg, 0.1329 mmol) and HCl (4 mL of 4 M, 16.00 mmol) (in dioxane) was stirred for one hour.
  • Example L Preparation of 3-[[4-[(2R)-2-aminopropoxy]-6-(2,6-dimethylphenyl)pyrimidin- 2-yl]sulfamoyl]benzoic acid
  • Step 1 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Solid sodium tert-butoxide (approximately 86.25 mg, 0.8975 mmol) was added after. The reaction mixture was allowed to stir overnight at room temperature. Acetic acid (approximately 64.68 mg, 61.25 ⁇ L, 1.077 mmol) was added. The reaction mixture was diluted with DCM and washed with HCl (1 M, 1 ⁇ 7 mL) and brine (2 ⁇ 75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 2 3-[[4-[(2R)-2-Aminopropoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid [00184] A solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (1.65 g, 2.964 mmol) in HCl (8 mL of 4 M, 32.00 mmol) (in dioxane) was stirred for two hours, and the solvent was removed under vacuum.
  • Example M Preparation of 3-[[4-[(2R)-2-amino-5-hydroxy-5-methyl-hexoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 Benzyl (4R)-4-(tert-butoxycarbonylamino)-5-hydroxy-pentanoate
  • N- methylmorpholine (3.0360 g, 3.3 mL, 30.016 mmol) was added followed by a slow addition of isobutyl chloroformate (4.1067 g, 3.9 mL, 30.069 mmol) such that the reaction temperature was kept below -10 °C.
  • the mixture was stirred for 30 minutes.
  • the solids were quickly filtered and washed with dimethoxyethane (30 mL).
  • the filtrate was cooled to -40 °C and a solution of sodium borohydride (1.45 g, 38.327 mmol) in water (15 mL) was added slowly such that the reaction temperature was maintained between -30 °C and -15 °C.
  • the mixture was stirred for 15 minutes.
  • Step 2 Benzyl 3-[(4R)-2-oxooxazolidin-4-yl]propanoate [00186] To a solution of benzyl (4R)-4-(tert-butoxycarbonylamino)-5-hydroxy-pentanoate (7.98 g, 24.652 mmol) in dichloroethane (80 mL) was added pyridine (48.900 g, 50 mL, 618.21 mmol). p-toluenesulfonic anhydride (8.65 g, 25.972 mmol) was then added and the mixture was stirred at room temperature for 1 hour and then heated to 90 oC for 2 hours.
  • Step 3 (4R)-4-(3-Hydroxy-3-methyl-butyl)oxazolidin-2-one
  • Methylmagnesium bromide 26 mL of 3 M, 78.000 mmol
  • diethyl ether was added to a mixture of toluene (42 mL) and tetrahydrofuran (42 mL) at –20 °C (methanol + water + dried ice).
  • Step 4 (2R)-2-Amino-5-methyl-hexane-1,5-diol
  • Step 5 3-[[4-[(2R)-2-Amino-5-hydroxy-5-methyl-hexoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00189] To a solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (371 mg, 0.8878 mmol) and (2R)-2-amino-5-methyl-hexane-1,5-diol (261 mg, 1.7729 mmol) in THF cooled down to 0°C was slowly added Sodium tert-butoxide (375 mg, 3.9020 mmol).
  • Step 2 1-(Benzyloxymethyl)-2-bromo-3-methyl-benzene [00191] To (2-bromo-3-methyl-phenyl)methanol (1.87 g, 9.301 mmol) in DMSO (38 mL) cooled to 0°C in an ice bath was added NaH (1.227 g of 60 %w/w, 30.68 mmol) and the reaction was stirred for 15 minutes. Then bromomethylbenzene (1.75 mL, 14.71 mmol) was added and the mixture was allowed warm to rt and stir for 16 h. The mixture was partitioned between EtOAc and water.
  • Step 3 2-[2-(Benzyloxymethyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane [00192]
  • the resulting brown oil was purified by silica gel column chromatography (220 gram column) using a gradient of 100% hexanes to 30% ethyl acetate in hexanes (compound elutes at 10% ethyl acetate) to obtain the desired compound as a white solid 2-[2-(benzyloxymethyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (4.63 g, 74%).
  • ESI-MS m/z calc.338.20532, found 339.4 (M+1) + ; Retention time: 2.23 minutes; LC method A.
  • Step 4 tert-Butyl N-[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin- 2-yl]-N-tert-butoxycarbonyl-carbamate [00193] tert-Butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (1.5 g, 4.118 mmol) and 2-[2-(benzyloxymethyl)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.4 g, 4.139 mmol) were combined in dimethoxyethane (36 mL) and water (6 mL).
  • Step 5 4-[2-(Benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-amine [00194] tert-Butyl N-[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-yl]-N- tert-butoxycarbonyl-carbamate (1.7 g, 3.148 mmol) was dissolved in DCM (35 mL) and to the mixture was added HCl (4M in dioxane) (21 mL of 4 M, 84.00 mmol) and the reaction was stirred at room temperature.
  • Step 6 Methyl 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2- yl]sulfamoyl]benzoate [00195] 4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2-amine (2.74 g, 8.063 mmol) was dissolved in THF (50 mL) and cooled in an ice bath to 0°C. methyl 3- chlorosulfonylbenzoate (2.85 g, 12.15 mmol) was added in one portion.
  • lithium tert-amoxide (7.25 mL of 40 %w/w, 22.50 mmol) was added dropwise and the reaction was allowed to slowly warm to room temperature. The reaction was stirred for 6 h . The mixture was pumped on high vacuum overnight, then re-subjected to dilution in THF (25 mL). After cooling in an ice bath to methyl 3-chlorosulfonylbenzoate (1.0 g) was added followed by the addition of lithium tert- amoxide (3 mL of 40 %w/w) added dropwise and the reaction was allowed to warm at room temperature for 4 hours. The mixture was acidified the addition of 1 HCl. The reaction mixture was extracted with ethyl acetate.
  • Step 7 3-[[4-[2-(Benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2- yl]sulfamoyl]benzoic acid [00196] Methyl 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin-2- yl]sulfamoyl]benzoate (2.06 g, 3.829 mmol) and NaOH (30 mL of 1 M, 30.00 mmol) were combined in THF (25 mL) and stirred at room temperature for 2 h.
  • Step 8 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-[2-(benzyloxymethyl)-6-methyl- phenyl]pyrimidin-2-yl]sulfamoyl]benzoic acid [00197] In a 500 mL flask, 3-[[4-[2-(benzyloxymethyl)-6-methyl-phenyl]-6-chloro-pyrimidin- 2-yl]sulfamoyl]benzoic acid (2.0 g, 3.817 mmol), (2R)-2-amino-4-methyl-pentan-1-ol (460 mg, 3.925 mmol) and THF (40 mL) were mixed and cooled in an ice bath at 0°C, to which KOtBu (2.15 g, 19.16 mmol) was added.
  • Example P Preparation of 6-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyridine-2-carboxylic acid
  • Step 1 6-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyridine-2-carboxylic acid
  • 6-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyridine-2-carboxylic acid 5.03 g, 12.01 mmol
  • (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (2.05 g, 12.23 mmol) were combined in THF (35 mL).
  • reaction mixture was poured in to 0.1 N HCl (500 mL), the pH adjusted to 4 with 1 N HCl and then extracted with EtOAc (3x). The organics were combined, washed with 0.1 N HCl, water, saturated aqueous sodium bicarbonate (2x), brine, dried over sodium sulfate and evaporated to dryness.
  • Step 2 (1R,2R)-2-Amino-3-cyclohexyl-1-cyclopropyl-propan-1-ol [00201]
  • Stage 1 A THF (12 mL) solution of tert-butyl N-[(1R)-1-(cyclohexylmethyl)-2- [methoxy(methyl)amino]-2-oxo-ethyl]carbamate (2.18 g, 6.933 mmol) was cooled to 0 °C using an ice-water bath and treated with a solution of LAH in THF (7 mL of 1 M, 7.00 mmol) dropwise.
  • Stage 2 The Stage 1 product from above was taken up in THF (12 mL), cooled to 0 °C and treated with bromo(cyclopropyl)magnesium in MeTHF (15 mL of 1 M, 15.00 mmol) and the reaction was warmed to room temperature and stirred for 2 h. Then, it was quenched with aqueous HCl (20 mL of 1 M, 20.00 mmol) and diluted with ethyl acetate (15 mL). The organic phase was separated and washed with water (10 mL) followed by brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • Stage 3 The Stage 2 product from above was treated with HCl in dioxane (approximately 1.733 mL of 4 M, 6.933 mmol), stirred at room temperature for 90 min and then concentrated in vacuo.
  • Step 3 (1R,2R)-3-Cyclohexyl-1-cyclopropyl-2-(spiro[2.3]hexan-5-ylamino)propan- 1-ol
  • spiro[2.3]hexan-5-one (13.2 mg, 0.1373 mmol) in DCM (0.5 mL) was added (1R,2R)-2-amino-3-cyclohexyl-1-cyclopropyl-propan-1-ol (hydrochloride salt) (33.7 mg, 0.1442 mmol), followed by sodium triacetoxyborohydride (51.2 mg, 0.2416 mmol) and the mixture was stirred for 3 h.
  • Step 4 3-[[4-[(1R,2R)-3-Cyclohexyl-1-cyclopropyl-2-(spiro[2.3]hexan-5- ylamino)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00205] A THF (2 mL) mixture of (1R,2R)-3-cyclohexyl-1-cyclopropyl-2-(spiro[2.3]hexan-5- ylamino)propan-1-ol (36.2 mg, 0.1305 mmol), 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (66.5 mg, 0.1591 mmol), and sodium t-butoxide (62.6 mg, 0.6514 mmol) was stirred at room temperature for 2 h.
  • Step 5 (10R,11R)-11-(Cyclohexylmethyl)-10-cyclopropyl-6-(2,6-dimethylphenyl)- 2,2-dioxo-12-spiro[2.3]hexan-5-yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 1) [00206] A DMF (1.8 mL) solution of 3-[[4-[(1R,2R)-3-cyclohexyl-1-cyclopropyl-2- (spiro[2.3]hexan-5-ylamino)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (13.5 mg, 0.01942 mmol), COMU (13.2 mg, 0.0
  • Example 2 Preparation of Compound 2 Step 1: 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde [00207] A solution of 2-bromo-3-methyl-benzaldehyde (22.5 g, 113.04 mmol) , bis(pinacolato)diboron (43.1 g, 169.73 mmol) , and KOAc (22.2 g, 226.20 mmol) in 1,4-dioxane (500 mL) was prepared.
  • Step 2 2-[(11R)-11-Isobutyl-3-(methoxymethyl)-2,2,13-trioxo-12-spiro[2.3]hexan-5- yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-6-yl]-3-methyl-benzaldehyde [00208] A heterogeneous solution of (11R)-6-chloro-11-isobutyl-3-(methoxymethyl)-2,2- dioxo-12-spiro[2.3]hexan-5-yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaen-13-one (90 mg, 0.1682 mmol) ,
  • Step 2 3-[[4-[(2R)-2-Amino-5-methyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid [00212]
  • Stage 1 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (1.495 g, 3.578 mmol), (2R)-2-amino-5-methyl-hexan-1-ol (hydrochloride salt) (1.2 g, 7.157 mmol), and Sodium tert-butoxide (1.725 g, 17.95 mmol) were combined in anhydrous THF (8.418 mL), and warmed to 60 °C for 15 (list 1) to 30 (list 2) minutes.
  • the reaction mixture was then cooled to room temperature, and Boc anhydride (1.565 g, 7.171 mmol) was added. After stirring at room temperature for 2 hours, additional Boc anhydride (700 mg, 3.207 mmol) and sodium tert-butoxide (600 mg, 6.243 mmol) were added and stirring was continued for an additional 2 hours.
  • the reaction mixture was poured into a separatory funnel containing 0.2 M HCl and ethyl acetate. The layers were separated, and the aqueous was extracted an additional 4x ethyl acetate, and the combined organics were washed with brine, dried over sodium sulfate and concentrated.
  • Stage 2 The resulting crude material was dissolved in dichloromethane (10 mL), HCl (18 mL of 4 M, 72.00 mmol) (in dioxane) was added and the reaction was stirred at room temperature for a 30 minutes, then concentrated under reduced pressure, suspended in dichloromethane and hexanes and concentrated a second time, before drying overnight under high vacuum to give as a white solid, 3-[[4-[(2R)-2-amino-5-methyl-hexoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (750 mg, 38%).
  • Step 3 (11R)-6-(2,6-Dimethylphenyl)-11-isopentyl-2,2-dioxo-12-spiro[2.3]hexan-5- yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 3) [00214] Stage 1: 3-[[4-[(2R)-2-amino-5-methyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (60 mg, 0.1093 mmol) and spiro[2.3]hexan-5-one (approximately 21.01 mg, 0.2186 mmol) were combined in dichloromethane (0.5 mL), and sodium triacetoxyborohydride
  • reaction mixture was stirred at room temperature for 1 hour, then a second portion of sodium triacetoxyborohydride (approximately 46.33 mg, 0.2186 mmol) was added, and the reaction mixture was stirred at room temperature for an additional hour. An additional portion of spiro[2.3]hexan-5-one (approximately 21.01 mg, 0.2186 mmol) was added, followed 30 minutes later by a third portion of sodium triacetoxyborohydride (approximately 46.33 mg, 0.2186 mmol). After a total of four hours reaction time, the reaction mixture was added to a separatory funnel containing ethyl acetate and 0.5 M HCl.
  • Stage 2 The crude product was combined with HATU (approximately 66.50 mg, 0.1749 mmol) in DMF and DIPEA (approximately 84.76 mg, 114.2 ⁇ L, 0.6558 mmol) was added. The reaction was stirred at room temperature for 3 hours. The reaction mixture was then added to a separatory funnel containing 25 mL 0.5 M HCl and 25 mL ethyl acetate.
  • Step 2 (11R)-6-(2,6-Dimethylphenyl)-12-[6-(2-hydroxypropan-2- yl)spiro[3.3]heptan-2-yl]-11-(3-methylbutyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione, more polar isomer peak 1 (Compound 4), and (11R)-6-(2,6-dimethylphenyl)- 12-[6-(2-hydroxypropan-2-yl)spiro[3.3]heptan-2-yl]-11-(3-methylbutyl)-9-ox
  • Methyl Magnesium Bromide (0.050 mL of 3 M, 0.1500 mmol) (3M solution in diethyl ether) was added dropwise. The reaction mixture was stirred in the ice bath for 5 min, then it was stirred at room temperature for 4 h. The mixture was cooled down in ice and quenched by adding an aqueous saturated solution of ammonium chloride (5 drops) and DMSO (1 mL).
  • Example 5 Preparation of Compound 6 Step 1: Iodo-1-(2-methoxyethyl)pyrazole [00219] 4-Iodo-1H-pyrazole (2 g, 10.31 mmol) was combined with cesium carbonate (5.1 g, 15.65 mmol) in anhydrous acetonitrile (15 mL).1-Bromo-2-methoxy-ethane (1.15 mL, 12.24 mmol) was added and the reaction mixture was stirred vigorously at room temperature for 18 hours. The reaction mixture was then filtered through Celite, eluting with acetonitrile. The filtrate was concentrated, then dissolved in diethyl ether and filtered through Celite a second time.
  • Step 2 (2R)-2-[[1-(2-Methoxyethyl)pyrazol-4-yl]amino]-5-methyl-hexan-1-ol
  • 4-Iodo-1-(2-methoxyethyl)pyrazole (approximately 150.3 mg, 0.5965 mmol) was combined with the (2R)-2-amino-5-methyl-hexan-1-ol (hydrochloride salt) (100 mg, 0.5964 mmol), CuI (approximately 11.36 mg, 0.05965 mmol), and NaOH (approximately 95.43 mg, 2.386 mmol) (ground with mortar and pestle) in a screw cap vial, which was then purged with nitrogen.
  • the product was dissolved in DMF (8 mL) and NMM (approximately 122.7 mg, 133.4 ⁇ L, 1.213 mmol) was added. The reaction mixture was cooled to 0 °C and CDMT (approximately 79.87 mg, 0.4549 mmol) was added. The reaction was allowed to warm to room temperature as the ice melted and stirred for 48 hours.
  • the product was dissolved in DMF (8 mL) and NMM (approximately 162.0 mg, 176.1 ⁇ L, 1.602 mmol) was added. The reaction mixture was cooled to 0 °C and CDMT (approximately 70.32 mg, 0.4005 mmol) was added. The reaction was allowed to warm to room temperature as the ice melted and stirred for 48 hours.
  • Example 7 Preparation of Compound 8 and Compound 9 Step 1: Methyl 2-(tert-butoxycarbonylamino)-5,5-dimethyl-hex-2-enoate [00224] To a stirred solution of methyl 2-(tert-butoxycarbonylamino)-2- dimethoxyphosphoryl-acetate (2.86 g, 9.6218 mmol) and DBU (1.4252 g, 1.4 mL, 9.3617 mmol) in DCM (20 mL) was added 3,3-dimethylbutyraldehyde (997.50 mg, 1.25 mL, 8.7358 mmol). The reaction mixture was stirred at room temperature for 16 h.
  • Step 2 Methyl (2R)-2-(tert-butoxycarbonylamino)-5,5-dimethyl-hexanoate [00225] To a solution of methyl (E)-2-(tert-butoxycarbonylamino)-4,5,5-trimethyl-hex-2- enoate (2 g, 7.0082 mmol) in ethanol (27 mL) and 1,4-dioxane (9 mL) was bubbled nitrogen for 5 min.
  • Step 3 tert-Butyl N-[(1R)-1-(hydroxymethyl)-4,4-dimethyl-pentyl]carbamate [00226] To a solution of methyl (2R)-2-(tert-butoxycarbonylamino)-5,5-dimethyl-hexanoate (1.9 g, 6.9503 mmol) in THF (20 mL) was added LiBH4 (2 M solution in THF) (8.8 mL of 2 M, 17.600 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was then poured slowly over a saturated aqueous solution of ammonium chloride (50 mL) at 0°C (strong evolution of gas, but no exotherm).
  • Step 4 (2R)-2-Amino-5,5-dimethyl-hexan-1-ol [00227]
  • tert-butyl N-[(1R)-1-(hydroxymethyl)-4,4-dimethyl-pentyl]carbamate (1.72 g, 7.0102 mmol) in 1,4-dioxane (9 mL) was added hydrogen chloride (4 N in 1,4-dioxane) (9 mL of 4 M, 36.000 mmol).
  • the reaction mixture was stirred at room temperature for 16 h.
  • the solid was dried in vacuo to provide the product (3.3 g, 99%) as an off-white solid.
  • the product was further purified by reverse phase chromatography on a 120 g C 18 cartridge using a gradient of 10-100% MeOH in water (with 0.1% HCl) to afford after lyophilization in water (15 mL) and MeCN (10 mL) 3-[[4-[(2R)-2-amino-5,5-dimethyl- hexoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (2.37 g, 70%) as a pale pink solid.
  • Step 7 Methyl 2-[(11R)-11-(3,3-dimethylbutyl)-6-(2,6-dimethylphenyl)-2,2,13- trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-12-yl]spiro[3.3]heptane-6-carboxylate [00230] 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-2-[(6-methoxycarbonylspiro[3.3]heptan-2- yl)amino]-5,5-dimethyl-hexoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (243 mg, 0.3397 mmol) was dissolved in DMF (2.4 mL).
  • N-methylmorpholine (57 ⁇ L, 0.5185 mmol) was added, and the solution was cooled to 0 °C before the addition of 2-chloro-4,6- dimethoxy-1,3,5-triazine (78 mg, 0.4443 mmol).
  • the reaction mixture was allowed to warm to room temperature, stirred for 3 hours and stored overnight in a 4 °C refrigerator.
  • the reaction mixture was then diluted with EtOAc (50 mL) and washed with aqueous HCl (1 ⁇ 50 mL). The aqueous layer was further extracted with EtOAc (2 ⁇ 50 mL). All organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 8 (11R)-11-(3,3-Dimethylbutyl)-6-(2,6-dimethylphenyl)-12-[6-(1-hydroxy-1- methyl-ethyl)spiro[3.3]heptan-2-yl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one, less polar isomer (Compound 8), and (11R)-11-(3,3-dimethylbutyl)-6-(2,6-dimethylphenyl)-12- [6-(1-hydroxy-1-methyl-ethyl)spir
  • Step 3 4-Chloro-6-(4-fluoro-2,6-dimethyl-phenyl)pyrimidin-2-amine [00234] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(4-fluoro-2,6- dimethyl-phenyl)pyrimidin-2-yl]carbamate (9.05 g, 20.026 mmol) in DCM (100 mL) was added TFA (29.600 g, 20 mL, 259.60 mmol) and the reaction was stirred for 2 h at room temperature.
  • Step 4 Methyl 3-[[4-chloro-6-(4-fluoro-2,6-dimethyl-phenyl)pyrimidin-2- yl]sulfamoyl]benzoate [00235] To a solution of 4-chloro-6-(4-fluoro-2,6-dimethyl-phenyl)pyrimidin-2-amine (2.78 g, 11.045 mmol) in THF (40 mL) at 0°C was added methyl 3-chlorosulfonylbenzoate (4.32 g, 18.410 mmol).
  • Lithium tert-amoxide (6.1320 g, 21 mL of 40 %w/w, 26.071 mmol) was added to the solution dropwise keeping the temperature below 5°C. The solution was allowed to warm to room temperature while it stirred overnight. The solution was acidified with 2M HCl (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (200 mL) and dried over sodium sulfate.
  • Step 5 3-[[4-Chloro-6-(4-fluoro-2,6-dimethyl-phenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid [00236] To a solution of methyl 3-[[4-chloro-6-(4-fluoro-2,6-dimethyl-phenyl)pyrimidin-2- yl]sulfamoyl]benzoate (792 mg, 1.7605 mmol) in THF (50 mL) was added an aqueous solution of NaOH (10 mL of 1 M, 10.000 mmol) and stirred for 1 hour at room temperature.
  • the solution was washed with diethyl ether (2x100 mL) before being acidified using 1M HCl (50 mL) and extracted with ethyl acetate (2x200 mL) before being washed with brine (200 mL).
  • the organic layer was dried over sodium sulfate and concentrated in vacuum before being purified by prep- hplc using TFA as a buffer.
  • the pure fractions were combined and extracted with ethyl acetate (3x150mL) and then washed with brine (150 mL).
  • Step 6 3-[[4-(4-Fluoro-2,6-dimethyl-phenyl)-6-[(2R)-4-methyl-2-(spiro[2.3]hexan-5- ylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00237] 3-[[4-Chloro-6-(4-fluoro-2,6-dimethyl-phenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (76.2 mg, 0.1748 mmol), (2R)-4-methyl-2-(spiro[2.3]hexan-5-ylamino)pentan-1-ol (hydrochloride salt) (41.2 mg, 0.1762 mmol), and sodium tert-butoxide (85.2 mg, 0.8865 mmol) were combined in THF (1 mL) and stirred at room temperature for 1.5 h.
  • Step 7 (11R)-6-(4-Fluoro-2,6-dimethyl-phenyl)-11-isobutyl-2,2-dioxo-12- spiro[2.3]hexan-5-yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 10) [00238] 3-[[4-(4-Fluoro-2,6-dimethyl-phenyl)-6-[(2R)-4-methyl-2-(spiro[2.3]hexan-5- ylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (102 mg, 0.1611 mmol), HATU (70.5 mg, 0.1854 mmol), and triethylamine (90 ⁇ L
  • reaction mixture was filtered and purified by reverse-phase HPLC utilizing a gradient of 1-99% acetonitrile in 5 mM aqueous HCl to yield (11R)-6-(4-fluoro-2,6-dimethyl-phenyl)-11-isobutyl-2,2-dioxo-12- spiro[2.3]hexan-5-yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (45.1 mg, 48%) ESI-MS m/z calc.578.2363, found 579.2 (M+1) + ; Retention time: 2.1 minutes, LC method A.
  • Example 9 Preparation of Compound 11 and Compound 12 Step 1: tert-Butyl 2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-7- azaspiro[3.5]nonane-7-carboxylate [00239] (2R)-2-amino-4-methyl-pentan-1-ol (63 mL, 522.0 mmol) was added to a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (100 g, 417.9 mmol) in anhydrous DCE (715 mL) under nitrogen and stirred at rt for 15 minutes.
  • Sodium triacetoxyborohydride (266 g, 1.255 mol) was divided into 3 separate portions and added while keeping the temperature below 27°C, then stirred at rt for 18 hours. The mixture was cooled to 4°C, then HCl (420 mL of 4 M, 1.680 mol) was added very slowly, keeping the temperature between 4°C and 12°C (large delayed exotherm, gas evolution, and foaming in the beginning of the HCl addition). A solution of potassium carbonate (694 g, 5.022 mol) in water (650 mL) was added, while keeping the temperature below 10°C, then another portion of water (600 mL) was added, followed by MTBE (715 mL).
  • Step 2 3-[[4-[(2R)-2-[(7-tert-Butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)amino]-4- methyl-pentoxy]-6-chloro-pyrimidin-2-yl]sulfamoyl]benzoic acid [00240] tert-Butyl 2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-7- azaspiro[3.5]nonane-7-carboxylate (hydrochloride salt) (1.042 g, 2.764 mmol) and 3-[(4,6- dichloropyrimidin-2-yl)sulfamoyl]benzoic acid (960.4 mg, 2.758 mmol) were combined in THF (19 mL).
  • Step 3 tert-Butyl 2-[(11R)-6-chloro-11-isobutyl-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaen-12-yl]-7- azaspiro[3.5]nonane-7-carboxylate [00241] 3-[[4-[(2R)-2-[(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)amino]-4-methyl- pentoxy]-6-chloro-pyrimidin-2-yl]sulfamoyl]benzoic acid (1.01 g, 1.549 mmol), HATU (591 mg, 1.554 mmol), and triethylamine (875 ⁇ L, 6.278 mmol) were combined in DMF (10
  • reaction mixture was partitioned between ethyl acetate (20 mL) and a 1M HCl solution (20 mL). The organics were separated, washed with brine (2 x 20 mL), dried over sodium sulfate and evaporated.
  • Step 4 tert-Butyl 2-[(11R)-11-isobutyl-6-(2-isopropylphenyl)-2,2,13-trioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaen- 12-yl]-7-azaspiro[3.5]nonane-7-carboxylate (Compound 12) [00242] tert-Butyl 2-[(11R)-6-chloro-11-isobutyl-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaen-12-yl]-7- azaspiro[3.5]nonane-7-carboxylate
  • reaction mixture was filtered and purified by LC/MS utilizing a gradient of 1-99% acetonitrile in 5 mM aqueous HCl to yield tert-butyl 2-[(11R)-11-isobutyl-6-(2- isopropylphenyl)-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaen-12-yl]-7-azaspiro[3.5]nonane-7-carboxylate (13.4 mg, 22%) ESI- MS m/z calc.717.356, found 718.4 (M+1) + ; Retention time: 0.84 minutes, LC method D.
  • Step 5 (11R)-12-(7-Azaspiro[3.5]nonan-2-yl)-11-isobutyl-6-(2-isopropylphenyl)-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaen-13-one [00243] tert-Butyl 2-[(11R)-11-isobutyl-6-(2-isopropylphenyl)-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaen-12-yl]-7- azaspiro[3.5]nonane-7-carboxylate (11 mg, 0.01532 mmol
  • Step 6 (11R)-11-Isobutyl-6-(2-isopropylphenyl)-12-(7-methyl-7-azaspiro[3.5]nonan- 2-yl)-2,2-dioxo-9-oxa-2 ⁇ 6-thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaen-13-one (Compound 11) [00244] (11R)-12-(7-Azaspiro[3.5]nonan-2-yl)-11-isobutyl-6-(2-isopropylphenyl)-2,2-dioxo- 9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaen-13- one (hydrochloride salt) (10 mg, 0.0
  • Example 10 Preparation of Compound 13 and Compound 14 Step 1: tert-Butyl 2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-7- azaspiro[3.5]nonane-7-carboxylate [00245] (2R)-2-Amino-4-methyl-pentan-1-ol (4.0 mL, 31.30 mmol) was added to a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5.00 g, 20.89 mmol) in anhydrous DCE (30 mL) under nitrogen and stirred at rt for 30 minutes.
  • Step 2 3-[[4-[(2R)-2-[(7-tert-Butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)amino]-4- methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00246] NaOtBu (227.1 g, 2.363 mol) was added to THF (2,000 mL) at -25°C (exotherm).
  • Step 3 tert-Butyl 2-[(11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen- 12-yl]-7-azaspiro[3.5]nonane-7-carboxylate (Compound 13) [00247] 3-[[4-[(2R)-2-[(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)amino]-4-methyl- pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulf
  • the solution was stirred at room temperature for 13 hours.
  • the deep orange solution was evaporated under reduced pressure at 45-50 °C to an orange mass and treated with citric acid (550 mL of 1 M, 550.0 mmol) to give a light brown suspension which was stirred at room temperature for 2 h.
  • the solid was collected by filtration and the wet solid was dissolved in DCM, which was washed with 1M citric acid and brine and the aqueous phases were back extracted once with DCM.
  • the combined organic phases were dried (magnesium sulfate), treated with charcoal, filtered over Celite and evaporated to give 52.3g of a deep orange foam.
  • Example 12 Preparation of Compound 16 Step 1: (11R)-12-(7-Acetyl-7-azaspiro[3.5]nonan-2-yl)-6-(2,6-dimethylphenyl)-11- isobutyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 16) [00250] (11R)-12-(7-azaspiro[3.5]nonan-2-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo- 9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-
  • the reaction mixture was stirred at room temperature for 15 minutes then diluted with ethyl acetate and washed with aqueous 1M HCl. The aqueous layer was extracted two additional times with ethyl acetate, and the combined organics were washed with brine then dried over sodium sulfate and concentrated.
  • the resulting crude material was purified by silica gel chromatography using a gradient of 0-10% methanol in dichloromethane (elutes around 5% methanol).
  • Example 14 Preparation of Compound 18 Step 1: 7-(2,2,2-Trifluoroethyl)-7-azaspiro[3.5]nonan-2-one [00252] tert-Butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (250 mg, 1.045 mmol) was combined in dichloromethane (2.5 mL) with HCl (2.5 mL of 4 M, 10.00 mmol) and stirred for 30 minutes at room temperature. The reaction mixture was then concentrated to give a slightly yellow amorphous solid.
  • Step 2 (11R)6-(2,6-Dimethylphenyl)-11-isobutyl-2,2-dioxo-12-[7-(2,2,2- trifluoroethyl)-7-azaspiro[3.5]nonan-2-yl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 18) [00254] 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (50 mg, 0.09345 mmol) and 7-(2,2,2- trifluoroethyl)-7-azaspiro[3.5]nonan-2-one (approximately
  • Example 16 Preparation of Compound 20 Step 1: (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-2,2-dioxo-12-[7-(3,3,3- trifluoropropyl)-7-azaspiro[3.5]nonan-2-yl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 20) [00256] (11R)-12-(7-Azaspiro[3.5]nonan-2-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo- 9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,
  • Example 18 Preparation of Compound 22 Step 1: (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-12-[7-(2-methoxyethyl)-7- azaspiro[3.5]nonan-2-yl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 22) [00258] (11R)-12-(7-Azaspiro[3.5]nonan-2-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16
  • reaction mixture was heated to 55 °C for 20 hours.
  • the reaction mixture was cooled to room temperature, diluted with methanol, filtered, then purified by reverse phase HPLC (15-75ACN in water, HCl modifier, 15 min run).
  • reverse phase HPLC 15-75ACN in water, HCl modifier, 15 min run.
  • One of the main fractions overlapped with starting material and was re-purified by reverse phase HPLC (1-50% ACN in water, HCl modifier).
  • Example 19 Preparation of Compound 23 Step 1: (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-12-[7-(3-methoxypropyl)-7- azaspiro[3.5]nonan-2-yl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 23) [00259] (11R)-12-(7-Azaspiro[3.5]nonan-2-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo- 9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14
  • reaction mixture was filtered and purified by LC/MS utilizing a gradient of 1-99% acetonitrile in 5 mM aqueous HCl to yield (11R)-12- ⁇ 7-[2-(benzyloxy)acetyl]-7-azaspiro[3.5]nonan-2-yl ⁇ -6-(2,6-dimethylphenyl)-11-(2- methylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (16.4 mg, 56%).
  • Example 22 Preparation of Compound 26 Step 1: 2-[(11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12-yl]- N,N-dimethyl-7-azaspiro[3.5]nonane-7-carboxamide (Compound 26) [00263] (11R)-12-(7-Azaspiro[3.5]nonan-2-yl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16- he
  • Example 23 Preparation of Compound 27 Step 1: 3-[[4-[(2R)-2-(Cyclobutylamino)-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00264] To cyclobutanone (approximately 7.030 mg, 0.1003 mmol) was added a solution of 3- [[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (50 mg, 0.1003 mmol) in NMP (0.2 mL) and dichloromethane (0.4 mL).
  • Step 2 (11R)-12-cyclobutyl-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2l 6-thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen- 13-one (Compound 27) [00265] 3-[[4-[(2R)-2-(cyclobutylamino)-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid was dissolved in DMF. HATU was added.
  • Example 24 Preparation of Compound 28 Step 1: 3-[[4-[(2R)-2-[(3,3-Dimethylcyclobutyl)amino]-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) [00266] 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (40 mg, 0.07476 mmol) was combined with 3,3- dimethylcyclobutanone (approximately 22.01 mg, 0.2243 mmol) and acetic acid (approximately 35.92 mg, 34.02 ⁇ L, 0.5981 mmol) in DCE (0.4 mL) and stirred at room temperature for 20 minutes, at which point sodium
  • Step 2 (11R)-12-(3,3-Dimethylcyclobutyl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 28) [00267] 3-[[4-[(2R)-2-[(3,3-Dimethylcyclobutyl)amino]-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (11 mg, 0.01894 mmol) was combined with HATU (approximately 9.361 mg, 0.02462 mmol) in DMF (1 mL), and DIPEA (approximately 12.24
  • Step 2 (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-12-(2-oxaspiro[3.3]heptan-6-yl)- 2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 29) [00269] 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-4-methyl-2-(2-oxaspiro[3.3]heptan-6- ylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (15 mg, 0.02522 mmol) was combined with HATU (approximately 11.51 mg, 0.03026 mmol) in DMF (1 mL) and DIPEA (approximately
  • Step 2 (11R)-12-Cyclopentyl-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen- 13-one (Compound 30) [00271] 3-[[4-[(2R)-2-(cyclopentylamino)-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (10 mg, 0.01765 mmol) was combined with HATU (25 mg, 0.06575 mmol) in DMSO (1 mL) and DIPEA (30 ⁇ L, 0.1722 mmol) was added.
  • Example 27 Preparation of Compound 31 Step 1: (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-12-(7-oxaspiro[3.5]nonan-2-yl)- 2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 31) [00272] 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (50 mg, 0.09345 mmol) was combined with 7- oxaspiro[3.5]nonan-2-one (approximately 26.20 mg, 0.1869 mmol) in
  • Example 28 Preparation of Compound 32 Step 1: (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-spiro[3.3]heptan-2- yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 32) [00274] 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (80 mg, 0.1495 mmol) was combined with spiro[3.3]heptan-2-one (approximately 32.94 mg, 0.2990 mmol) in dichloromethane.
  • Example 29 Preparation of Compound 33 and Compound 34 Step 1: tert-Butyl 2-[(11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen- 12-yl]-6-azaspiro[3.4]octane-6-carboxylate [00276] 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (150 mg, 0.2803 mmol) and tert-butyl 2-oxo-6- azaspiro[3.4]octane-6-carboxy
  • Step 3 (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-12-(6-isopropyl-6- azaspiro[3.4]octan-2-yl)-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one, (hydrochloride salt), diastereomer 1 (Compound 33), and (11R)-6-(2,6- dimethylphenyl)-11-isobutyl-12-(6-isopropyl-6-azaspiro[3.4]octan-2-yl)-2,2-dioxo-9- oxa-2 ⁇ 6
  • the resulting crude material was combined with HATU (approximately 284.3 mg, 0.7476 mmol) in DMF (15 mL), and DIEA (approximately 241.6 mg, 325.6 ⁇ L, 1.869 mmol) was added.
  • the reaction mixture was stirred for 16 hours, then was poured into a separatory funnel containing ethyl acetate and 1M HCl. The layers were separated and the aqueous was extracted 3 additional times with ethyl acetate. The combined organics were washed with brine dried over sodium sulfate and concentrated.
  • Example 31 Preparation of Compound 36 Step 1: (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-12-[3-(4-methylpiperazine-1- carbonyl)cyclobutyl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 36) [00281] 3-[(11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12-yl]cyclobutanecarboxylic acid (15 mg, 0.0
  • Example 33 Preparation of Compound 38 and Compound 39 Step 1: tert-Butyl 3-[(11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen- 12-yl]pyrrolidine-1-carboxylate [00284] 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (300 mg, 0.5607 mmol) was combined with tert- butyl 3-oxopyrrolidine-1-carboxylate (approximately 155.8 mg, 0.8411 mmol) in
  • the resulting material was dissolved in 5 mL DMF and added dropwise to a stirring solution of COMU (approximately 480.1 mg, 1.121 mmol) and DIPEA (approximately 434.8 mg, 586.0 ⁇ L, 3.364 mmol) in sufficient DMF to give a final concentration of 0.01 M.
  • the reaction mixture was then stirred at room temperature for 16 hours. After this time the reaction mixture was partitioned between 1M HCl and ethyl acetate. The layers were separated and the aqueous was extracted an additional 3x with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated.
  • the compound was purified by chromatography on silica gel (0-100 ethyl acetate in hexanes) to give tert-butyl 3-[(11R)-6-(2,6- dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12-yl]pyrrolidine-1- carboxylate (101 mg, 28%).
  • Step 3 propan-2-yl 3-[(11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-2,2,13- trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaen-12-yl]pyrrolidine-1-carboxylate, diastereomer 1 (Compound 38), and propan-2-yl 3-[(11R)-6-(2,6-dimethylphenyl)-11-(2- methylpropyl)-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaen-12- yl]pyrrolidine-1-carboxylate, di
  • DIPEA (approximately 11.02 mg, 14.85 ⁇ L, 0.08530 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was then quenched with several drops of 1M HCl, partially concentrated, then diluted with 1:1 DMSO/methanol, and filtered.
  • Example 34 Preparation of Compound 40 Step 1: 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[[3- (hydroxymethyl)cyclobutyl]amino]-4-methyl-pentoxy]pyrimidin-2- yl]sulfamoyl]benzoic acid [00287] 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (40 mg, 0.08023 mmol) and 3-(hydroxymethyl)cyclobutanone (approximately 24.10 mg, 0.2407 mmol) were combined in DCE with acetic acid (approximately 38.54 mg, 36.50 ⁇ L, 0.6418 mmol) and stirred at room temperature for 20 minutes.
  • Step 2 (11R)-6-(2,6-Dimethylphenyl)-12-[3-(hydroxymethyl)cyclobutyl]-11- isobutyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 40) [00288] 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-2-[[3-(hydroxymethyl)cyclobutyl]amino]-4- methyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (20 mg, 0.03230 mmol) was combined with HATU (approximately 15.97 mg, 0.04199 mmol) in DMF (1 mL) and DIPEA (approximately 20.87
  • Step 3 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]-(methoxymethyl)sulfamoyl]benzoic acid [00291]
  • sodium tert-butoxide (1.75 g, 18.21 mmol) were combined in THF (7 mL) and stirred at room temperature for 2 h.
  • Step 4 (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-3-(methoxymethyl)-2,2-dioxo-9- oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16- hexaen-13-one [00292] 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]- (methoxymethyl)sulfamoyl]benzoic acid (hydrochloride salt) (797 mg, 1.376 mmol) was dissolved in DMF (6 mL) and added to a solution of HATU (640.2 mg, 1.684 mmol) and triethylamine (766 ⁇ L, 5.496 mmol) in DMF (7 mL).
  • the reaction was stirred at room temperature for 20 min.
  • the reaction mixture was poured into water (20 mL) and the resulting solid was collected via filtration.
  • the solids were dissolved in ethyl acetate and washed with a 1M HCl solution, then brine.
  • Step 5 (11R)-6-(2,6-Dimethylphenyl)-12-(1,1-dioxothietan-3-yl)-11-isobutyl-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 41) [00293] (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-3-(methoxymethyl)-2,2-dioxo-9-oxa-2 ⁇ 6 - thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (10 mg, 0.01906 mmol) was combined with 2H-thiete 1,1-dioxide (3
  • the heterogeneous mixture was stirred for 5 min while purging nitrogen through it, to form a uniform milky emulsion.
  • sodium tert-butoxide (6.46 g, 67.22 mmol) at once.
  • the reaction was stirred for 1 h at room temperature.
  • the reaction mixture was partitioned between ethyl acetate (150 mL) and an ice-cold hydrochloric acid (82 mL of 1 M, 82.00 mmol) (pH was about 2).
  • the aqueous layer was re-extracted with ethyl acetate (2 x 50 mL).
  • the reaction was stirred at that temperature for 30 min, then the bath was removed, and the reaction was allowed to warm to room temperature. After it was stirred overnight (15 h total time) DMF was removed under reduced pressure.
  • the concentrated reaction mixture was poured into a stirred solution of ice- water (150 mL) and hydrochloric acid (80 mL of 1.0 M, 80.00 mmol). The mixture was stirred for 20 min and the resulting pinkish solid was collected by vacuum filtration. The solid was dissolved in ethyl acetate (100 mL) and washed with 1M HCl (100 mL), brine (100 mL), then dried over sodium sulfate and evaporated.
  • Example 38 Preparation of Compound 45, Compound 46, and Compound 47 Step 1: 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(3-isopropoxycyclobutyl)amino]-4- methyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00298] 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (98.6 mg, 0.1843 mmol), 3- isopropoxycyclobutanone (31.5 mg, 0.2458 mmol), and sodium triacetoxyborohydride (104.5 mg, 0.5531 mmol) were combined in DCM (0.3 mL) and stirred at room temperature for 5 h.
  • DCM 0.3 mL
  • Step 2 (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-12-(3-isopropoxycyclobutyl)-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 47) [00299] 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(3-isopropoxycyclobutyl)amino]-4-methyl- pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (38.3 mg, 0.05918 mmol), HATU (27 mg, 0.07101 mmol), and triethylamine (29.68 ⁇ L, 0.2129 mmol) were combined in DMF (1
  • Step 3 (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-12-(3-isopropoxycyclobutyl)-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one, diastereomer 1 (Compound 45), and (11R)-6- (2,6-dimethylphenyl)-11-isobutyl-12-(3-isopropoxycyclobutyl)-2,2-dioxo-9-oxa-2 ⁇ 6 - thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13- one, diastereomer 2 (Compound 46) [00300] (11R)-6-
  • Peak 1 diastereomer 1 (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-12-(3- isopropoxycyclobutyl)-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (2.9 mg, 15%) ESI-MS m/z calc.592.2719, found 593.3 (M+1) + ; Retention time: 2.07 minutes (LC method A), and peak 2, diastereomer 2, (11R)-6- (2,6-dimethylphenyl)-11-isobutyl-12-(3-isopropoxycyclobutyl)-2,2-dioxo-9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetrazatricyclo[12.3.1
  • Example 39 Preparation of Compound 48 Step 1: (11R)-6-(2,6-Dimethylphenyl)-12-(3-hydroxycyclobutyl)-11-isobutyl-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaen-13-one [00301] In a 250 mL 3-necked flask, a stirred solution of (11R)-12-(3-benzyloxycyclobutyl)-6- (2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaen-13-one (7.0 g,
  • Step 2 [3-[(11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12- yl]cyclobutyl] N,N-dimethylcarbamate (Compound 48) [00302] (11R)-6-(2,6-Dimethylphenyl)-12-(3-hydroxycyclobutyl)-11-isobutyl-2,2-dioxo-9- oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18)
  • Step 2 [3-Methyl-3-(trifluoromethoxy)cyclobutoxy]methylbenzene
  • 3-Benzyloxy-1-methyl-cyclobutanol (9.23 g, 48.009 mmol) was dissolved in ethyl acetate (325 mL) then silver triflate (37.05 g, 144.20 mmol), Selectfluor (25.61 g, 72.292 mmol) and potassium fluoride (11.02 g, 189.68 mmol) were added.
  • the vessel was flushed with nitrogen and 2-fluoropyridine (14.100 g, 12.5 mL, 145.23 mmol) and trifluoromethyltrimethylsilane (20.683 g, 21.5 mL, 145.46 mmol) were added.
  • the mixture was allowed to stir for 3 days at room temperature under a nitrogen atmosphere.
  • the mixture was filtered through a pad of Celite, and dry loaded on to silica gel and purified by flash column chromatography using 0-30% ethyl acetate in hexanes. The appropriate fractions were collected to give [3-methyl-3-(trifluoromethoxy)cyclobutoxy]methylbenzene (2.58 g, 19%) as a colorless oil.
  • Step 4 (2R)-4-Methyl-2-[[3-methyl-3-(trifluoromethoxy)cyclobutyl]amino]pentan- 1-ol
  • 3-methyl-3-(trifluoromethoxy)cyclobutanol 100 mg, 0.5878 mmol
  • pyridine 119 mg, 1.5044 mmol
  • trifluoromethylsulfonyl trifluoromethanesulfonate 270 mg, 0.9570 mmol
  • Step 5 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-4-methyl-2-[[3-methyl-3- (trifluoromethoxy)cyclobutyl]amino]pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00307] (2R)-4-Methyl-2-[[3-methyl-3-(trifluoromethoxy)cyclobutyl]amino]pentan-1-ol (171 mg, 0.6699 mmol) and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (313 mg, 0.7490 mmol) were dissolved in THF (9 mL) then sodium tert-butoxide (654 mg, 6.8052 mmol) was added and the reaction stirred at room temperature for 1 hour.
  • Example 41 Preparation of Compound 51 Step 1: Benzyl 2-[(4R)-2-oxooxazolidin-4-yl]acetate [00311] To a solution of benzyl (3R)-3-(tert-butoxycarbonylamino)-4-hydroxy-butanoate (27.8 g, 89.864 mmol)benzyl (3R)-3-(tert-butoxycarbonylamino)-4-hydroxy-butanoate (27.8 g, 89.864 mmol) in 1,2-dichloroethane (250 mL) was added pyridine (65.526 g, 67 mL, 828.40 mmol) and the mixture was cooled to 0-5 °C.
  • Step 2 (4R)-4-(2-Hydroxy-2-methyl-propyl)oxazolidin-2-one
  • Bromo(methyl)magnesium in diethyl ether 105 mL of 3 M, 315.00 mmol
  • THF 150 mL
  • a warm THF (80 mL) solution of benzyl 2-[(4R)-2-oxooxazolidin-4-yl]acetate (18.1 g, 76.944 mmol) was then added dropwise maintaining the temperature below –10 oC.
  • the mixture was warm up to room temperature and stirred for 18 hours.
  • the mixture was added via canula to a solution of acetic acid (85 mL) in water (440 mL) at 0°C.
  • the resultant mixture was stirred for 1 hour at room temperature.
  • the layers were separated.
  • the aqueous layer was saturated with brine (200 mL) and further extracted with 2-methyltetrahydrofuran (3 x 250 mL) and with ethanol/chloroform (1/2, 3 x 330 mL).
  • the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated.
  • the residue was co-evaporated with heptanes (4 x 100 mL).
  • Step 4 3-[[4-[(2R)-2-Amino-4-hydroxy-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00314] To a solution of (2R)-2-amino-4-methyl-pentane-1,4-diol (567 mg, 4.2571 mmol) and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (1.5 g, 3.5897 mmol) in tetrahydrofuran (6 mL) was slowly added sodium tert-butoxide in tetrahydrofuran (7.2 mL of 2 M, 14.400 mmol) and the mixture was stirred at room temperature for one hour.
  • the reaction was partitioned between ethyl acetate (30 mL) and 1 N hydrochloric acid (30 mL). The aqueous phase was extracted with ethyl acetate (2 x 20 mL) and 2-methyltetrahydrofuran (4 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated with ethyl acetate (20 mL), the precipitate was filtered and washed with ethyl acetate (2 x 10 mL).
  • reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride (20 mL). The aqueous phase was separated and washed with ethyl acetate (20 mL).
  • Step 6 (11R)-6-(2,6-Dimethylphenyl)-11-(2-hydroxy-2-methyl-propyl)-2,2-dioxo-12- spiro[2.3]hexan-5-yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 51) [00316] To a solution of 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-4-hydroxy-4-methyl-2- (spiro[2.3]hexan-5-ylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (110 mg, 0.1850 mmol) and triethyl amine (72.600 mg, 0.1 mL, 0.7175 mmol) in DMF (1.5 mL) and e
  • Example 42 Preparation of Compound 52 Step 1: 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-5-hydroxy-5-methyl-2-(spiro[2.3]hexan- 5-ylamino)hexoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00317] 3-[[4-[(2R)-2-Amino-5-hydroxy-5-methyl-hexoxy]-6-(2,6-dimethylphenyl)pyrimidin- 2-yl]sulfamoyl]benzoic acid (50 mg, 0.0875 mmol), spiro[2.3]hexan-5-one (44 mg, 0.4577 mmol) and acetic acid (4.0128 mg, 3.8 ⁇ L, 0.0668 mmol) were stirred at room temperature for 1 hour in acetonitrile (1 mL) and Methanol (0.6 mL).
  • the product was purified by normal phase chromatography (silica 12g) using a gradient of 0-18% MeOH in DCM to provide 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-5-hydroxy-5- methyl-2-(spiro[2.3]hexan-5-ylamino)hexoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (45.8 mg, 86%)as a white solid.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.40 (br.
  • Step 2 (11R)-6-(2,6-Dimethylphenyl)-11-(3-hydroxy-3-methyl-butyl)-2,2-dioxo-12- spiro[2.3]hexan-5-yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 52) [00318] To a solution of 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-5-hydroxy-5-methyl-2- (spiro[2.3]hexan-5-ylamino)hexoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (100 mg, 0.1643 mmol) in DMF (1.5000 mL) and EtOAc (5.5000 mL) was added TEA (108.90 mg, 0.15 mL
  • the product in DMF was directly injected on reverse phase column and purified by reverse phase chromatography (50g C18) using a gradient of 5% to 60% acetonitrile in water to provide after freeze drying (11R)-6-(2,6-dimethylphenyl)-11-(3-hydroxy-3-methyl-butyl)-2,2-dioxo-12- spiro[2.3]hexan-5-yl-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (50.1 mg, 51%) as a white fluffy solid .
  • Step 2 tert-Butyl N-[3-[(11R)-6-(2,6-dimethylphenyl)-2,2,13-trioxo-11-[[1- (trifluoromethyl)cyclopropyl]methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12- yl]cyclobutyl]carbamate [00320] In a 500 mL flask, to a stirred solution of 3-[[4-[(2R)-2-[[3-(tert- butoxycarbonylamino)cyclobutyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6- di
  • the tea-colored reaction was concentrated under reduced pressure at 35 oC (water-bath temperature) and the residue was poured into an ice-cold aqueous solution of citric acid (65 mL of 10 %w/v, 33.83 mmol).
  • the product was extracted with ethyl acetate (3 x 100 mL). The combined organics were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 3 tert-Butyl N-[3-[(11R)-6-(2,6-dimethylphenyl)-2,2,13-trioxo-11-[[1- (trifluoromethyl)cyclopropyl]methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaen-12- yl]cyclobutyl]carbamate, major diastereomer 1 (Compound 54), and tert-butyl N- [3-[(11R)-6-(2,6-dimethylphenyl)-2,2,13-trioxo-11-[[1- (trifluoromethyl)cyclopropyl]methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4,
  • the vial was briefly purged with nitrogen and the capped vial was stirred at ambient temperature for 1 h. Then 3 drops of methanol was added and the volatiles were removed under reduced pressure. The residue was taken up in DMSO (1 mL) and the solution was microfiltered through a Whatman 0.45 uM PTFE syringe filter disc and purified by preparative reverse phase HPLC (C 18 ) using 1-99% acetonitrile in water over 15 min (HCl as a modifier).
  • Example 44 Preparation of Compound 59 Step 6: isopropyl N-[3-[(11R)-6-(2,6-dimethylphenyl)-2,2,13-trioxo-11-[[1- (trifluoromethyl)cyclopropyl]methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12- yl]cyclobutyl]carbamate (Compound 59) [00326] To a stirred solution of (11R)-12-(3-aminocyclobutyl)-6-(2,6-dimethylphenyl)-2,2- dioxo-11-[[1-(trifluoromethyl)cyclopropyl]methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14
  • Methyl 6-chlorosulfonylpyrazine- 2-carboxylate 13.64 g, 57.642 mmol
  • MeTHF 25 mL
  • lithium tert-butoxide 17 mL of 3.1 M, 52.700 mmol
  • the ice bath was removed, and the mixture was stirred for 3 hours at room temperature.1N aqueous hydrochloric acid solution (50 mL) was added and the phases was separated.
  • the aqueous phase was extracted with MeTHF (50 mL) and the organic phase were combined, washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by silica-gel column chromatography on a 330 g column, eluting from 0% to 30% of ethyl acetate in heptanes to afford methyl 6-[[4-chloro-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyrazine-2-carboxylate (4.85 g, 18%) as an off-white solid.
  • Step 2 6-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyrazine-2- carboxylic acid
  • aqueous phase was acidified to pH ⁇ 3 with 3N aqueous hydrochloric acid solution and extracted with ethyl acetate (3 x 125 mL). The combined organic layers were washed with brine (125 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6-[[4- chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyrazine-2-carboxylic acid (4.4 g, 87%) as a yellow solid.
  • Step 3 6-[[4-(2,6-Dimethylphenyl)-6-[(2R)-4-methyl-2-(spiro[2.3]hexan-5- ylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]pyrazine-2-carboxylic acid [00331] In a 100 mL flask, 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyrazine-2-carboxylic acid (272 mg, 0.6479 mmol) and (2R)-4-methyl-2- (spiro[2.3]hexan-5-ylamino)pentan-1-ol (hydrochloride salt) (153 mg, 0.6545 mmol) were charged under nitrogen with anhydrous THF (2 mL) (suspension).
  • the solution was microfiltered through a syringe filter disc and purified by reverse phase preparative HPLC (C 18 ) using a gradient of acetonitrile in water (1 to 99% over 15 min) and HCl as a modifier. Evaporation gave a residue that was triturated in DCM/hexanes.
  • Step 2 Propan-2-yl N- ⁇ 3-[(11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-2,2,13- trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaen-12-yl]cyclobutyl ⁇ carbamate (Compound 63) [00336] (11R)-12-(3-aminocyclobutyl)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (hydrochloride salt) (11 mg, 0.
  • reaction was allowed to warm to ambient temperature and stirring continued for 14 h (overnight).
  • the reaction was diluted with ether (100 mL) and saturated aqueous sodium bicarbonate (30 mL) was added very slowly (to mitigate CO2 gas evolution). Then 10% sodium thiosulfate (25 mL) was added and stirred at ambient temperature for 20 min. The layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL).
  • Example 55 Preparation of Compound 71 Step 1: (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-[3-(tetrahydropyran- 4-ylamino)cyclobutyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13- one(Compound 71) [00344] In a 4 mL vial, to a stirred solution of tetrahydropyran-4-amine (8 mg, 0.07909 mmol) in anhydrous dichloromethane (0.5 mL) were added (11R)-6-(2,6-dimethylphenyl)-11-isobutyl- 2,2-dioxo-12-(3-oxocyclobutyl)-9-oxa-2 ⁇ 6
  • Step 2 Ethyl 2-methyl-5-nitro-pyrazole-3-carboxylate [00348] To a solution of ethyl 3-nitro-1H-pyrazole-5-carboxylate (29.6 g, 154.61 mmol) in DMF (200 mL) at 0°C was added potassium carbonate (44.2 g, 319.81 mmol) and iodomethane (34.200 g, 15 mL, 240.95 mmol) dropwise over 15 min. The mixture was stirred at rt overnight. The mixture was cooled with ice-water bath and cold water (600 mL) was added. The precipitate was collected by filtration and washed with cold water.
  • Step 3 Ethyl 5-amino-2-methyl-pyrazole-3-carboxylate [00349] A mixture of ethyl 2-methyl-5-nitro-pyrazole-3-carboxylate (24.74 g, 124.22 mmol), 10% Palladium on carbon 50% wet (8 g, 3.7587 mmol) and MeOH (250 mL) was hydrogenated under hydrogen (balloon) for 24 h. The mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to give ethyl 5-amino-2-methyl-pyrazole-3- carboxylate (20.88 g, 99%) as white solid.
  • the mixture was cooled to -5°C and a solution of sodium nitrite (9.26 g, 134.21 mmol) in water (50 mL) was added dropwise over 30 minutes, keeping the inner temperature between -6°C and -3°C.
  • the mixture was stirred at -5°C for 30 minutes, cooled to -10°C, and slowly canulated ( ⁇ 25 minutes) to the first solution.
  • the resulting mixture was stirred at 0-5°C (ice-water bath) for 90 minutes. More copper(I) chloride (270 mg, 2.7273 mmol) was added and the resulting mixture was stirred at 0-5°C (ice-water bath) for 1 hour.
  • Step 5 Ethyl 5-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-2- methyl-pyrazole-3-carboxylate [00351] To a solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (4.8 g, 20.539 mmol) in THF (140 mL) at 0°C was added a solution of ethyl 5-chlorosulfonyl-2-methyl- pyrazole-3-carboxylate (6.13 g, 23.217 mmol), followed by sodium tert-amoxide in toluene (13.9 mL of 40 %w/v, 50.486 mmol) dropwise.
  • the mixture was stirred at rt for 1.5 h.
  • the mixture was slowly poured into a 1 N aqueous HCl (50 mL) at 0 °C.
  • the mixture was diluted with water 100 mL and extracted with EtOAc (3x 100 mL). The combined organic layers were dried over sodium sulfate filtered and concentrated to dryness.
  • Step 6 5-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-2-methyl- pyrazole-3-carboxylic acid [00352] To a solution of ethyl 5-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]- 2-methyl-pyrazole-3-carboxylate (7.62 g, 16.598 mmol) in THF (220 mL) at 0°C was added a solution of NaOH (2.7 g, 67.505 mmol) in water (50 mL) and the mixture was stirred for 20 minutes.
  • Step 7 5-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]-2-methyl-pyrazole-3-carboxylic acid [00353] 5-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-2-methyl-pyrazole-3- carboxylic acid (250 mg, 0.5926 mmol) and (2R)-2-amino-4-methyl-pentan-1-ol (100 ⁇ L) were combined in THF (1.3 mL) and stirred until the reaction mixture became homogeneous.
  • Step 8 (10R)-15-(2,6-Dimethylphenyl)-10-isobutyl-6-methyl-3,3-dioxo-9- spiro[2.3]hexan-5-yl-12-oxa-3 ⁇ 6 -thia-2,5,6,9,16,17- hexazatricyclo[11.3.1.14,7]octadeca-1(17),4,7(18),13,15-pentaen-8-one (Compound 74) [00354] 5-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]-2-methyl-pyrazole-3-carboxylic acid (hydrochloride salt) (40 mg, 0.07420 mmol) was combined with the spiro[2.3]hexan-5-one (approximately 10.70 mg, 0.1113 mmol) in DCM (0.3 mL
  • reaction was stirred for 1 hour at room temperature, then additional sodium triacetoxyborohydride (approximately 47.18 mg, 0.2226 mmol) was added. After an additional 2 hours at room temperature the reaction mixtures were partitioned between 1M HCl and ethyl acetate. The layers were separated and the aqueous was extracted an additional 4x with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated to give crude reductive amination product, which was used in the next step without further purification.
  • the crude material was dissolved in DMF (5 mL) and added at a rapid dropwise to a stirring solution of HATU (approximately 56.43 mg, 0.1484 mmol) and DIPEA (approximately 57.54 mg, 77.55 ⁇ L, 0.4452 mmol) in DMF (10 mL).
  • the reaction mixture was stirred for 6 hours at room temperature.
  • the reaction mixture was then partitioned between 1M HCl and ethyl acetate. The layers were separated and the aqueous was extracted an additional 3x with ethyl acetate.
  • the combined organics were washed with brine, dried over sodium sulfate and concentrated.
  • Example 59 Preparation of Compound 75 Step 1: 3-[[4-[(2R)-2-[[2-(tert-Butoxycarbonylamino)spiro[3.3]heptan-6-yl]amino]- 5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid
  • the vial was briefly purged with nitrogen and the mixture was stirred at rt for 3.5 hours.
  • the mixture was treated with DCM (40 mL), 1N aqueous HCl and brine (total 30 mL) resulting in an aqueous phase and a thick dense gel.
  • the gel was separated, and the aqueous phase was further extracted with ethyl acetate (2x 20 mL-no product detected in the aqueous phase). Mixing the ethylacetate and the gel resulted in two phases that were easily separated.
  • the organic phase was dried over sodium sulfate and the solvents were evaporated.
  • Step 2 tert-butyl N- ⁇ 6-[(11R)-6-(2,6-dimethylphenyl)-2,2,13-trioxo-11-(3,3,3- trifluoro-2,2-dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaen-12- yl]spiro[3.3]heptan-2-yl ⁇ carbamate, diastereomer 1, and tert-butyl N- ⁇ 6-[(11R)-6- (2,6-dimethylphenyl)-2,2,13-trioxo-11-(3,3,3-trifluoro-2,2-dimethylpropyl)-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca
  • the mixture was stirred at room temperature for 41 hours (at 24 hours, approximatively half the cyclization was complete).
  • the mixture was concentrated and diluted with DMSO (3 mL).
  • the solution was microfiltered through a syringe filter disc and purified by reverse phase preparative HPLC (C 18 ) using a gradient of acetonitrile in water (1 to 99% over 15 min) and HCl as a modifier.
  • the pure fractions were collected and Brine and saturated bicarbonate were added.
  • the organic phase was evaporated and the white precipitate was extracted with EtOAc (2 x 30 mL).
  • the solution was microfiltered through a syringe filter disc and purified by reverse phase preparative HPLC (C 18 ) using a gradient of acetonitrile in water (1 to 99% over 15 min) and HCl as a modifier. Genevac evaporation provided a solid that was transferred using EtOAc.
  • Example 60 Preparation of Compound 76 Step 1: Methyl N- ⁇ 6-[(11R)-6-(2,6-dimethylphenyl)-2,2,13-trioxo-11-(3,3,3-trifluoro- 2,2-dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaen-12-yl]spiro[3.3]heptan-2-yl ⁇ carbamate, diastereomer 2 (Compound 76) [00359] A 100 mL flask containing tert-butyl N- ⁇ 6-[(11R)-6-(2,6-dimethylphenyl)-2,2,13- trioxo-11-(3,3,3-trifluoro-2,2-dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,
  • the solution was microfiltered through a syringe filter disc and purified by reverse phase preparative HPLC (C 18 ) using a gradient of acetonitrile in water (1 to 99% over 15 min) and HCl as a modifier. Genevac evaporation provided a 94% pure material (26 mg). It was dissolved in DCM and purified by flash chromatography on silica gel (4 g column) using a gradient of ethyl acetate (10 to 100% over 15 min) in hexanes. The product eluted around 60-70% EA.
  • the mixture was cooled with an ice-water bath and quenched with water (1000 mL) and stirred for 10 min.
  • To the mixture was added HCl (110 mL of 12 M, 1.320 mol) portions followed by isopropyl acetate (1,000 mL).
  • the mixture was basified with NaOH (350 g of 50 %w/w, 4.375 mol) and the phases split.
  • the aqueous phase was extracted with isopropyl acetate (1,000 mL).
  • the combined organic phases were washed with 1 L of brine, dried over magnesium sulfate, filtered and concentrated in vacuo. During concentration the product began to precipitate out and was collected using a M frit.
  • the solid was washed twice with 50 mL of MTBE and the combined solids dried in vacuo at 45 oC.
  • the solid was diluted with MTBE (9 L) and TsOH (40 g, 232.3 mmol) was added.
  • TsOH 40 g, 232.3 mmol
  • the creamy, white slurry was stirred for 30 minutes.
  • the precipitate was collected using a M frit.
  • the solid was air dried for 16 h.
  • the solid was slurried with isopropyl acetate (700 mL) and NaOH (500 mL of 2 M, 1.000 mol) until homogenous.
  • the phases were separated, and the organic phase washed with 500 mL of brine.
  • aqueous phases were extracted with isopropyl acetate (700 mL) and the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to about 200 mL. The slurry was filtered and a second crop from the filtrate was also collected and were added to the first crop collected.
  • tert-Butyl N-[6-[[(1R)-1- (hydroxymethyl)-2-[1-(trifluoromethyl)cyclopropyl]ethyl]amino]spiro[3.3]heptan-2- yl]carbamate (108.7 g, 63%).
  • Step 2 3-[[4-[(2R)-2-[[2-(tert-Butoxycarbonylamino)spiro[3.3]heptan-6-yl]amino]-3- [1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid [00361] To a solution of tert-butyl N-[6-[[(1R)-1-(hydroxymethyl)-2-[1- (trifluoromethyl)cyclopropyl]ethyl]amino]spiro[3.3]heptan-2-yl]carbamate (108.7 g, 277.0 mmol) and 3-[[4-chloro-6-(2,6-dimethylphenyl)
  • the addition was exothermic, and the reaction temperature was controlled using addition rate of the base.
  • the reaction was stirred for 1 hour at room temperature.
  • the reaction was quenched with the slow addition of HCl (800 mL of 2 M, 1.600 mol) and it was stirred for 5 min.
  • the mixture was transferred to a separatory funnel using 2Me-THF.
  • the aqueous phase was separated, and the organic phase washed with 500 mL of brine.
  • the combined aqueous phases were extracted with 500 mL of 2Me-THF.
  • the combined organic phases were dried over magnesium sulfate, filtered over Celite and the hazy solution concentrated in vacuo.
  • Step 3 tert-butyl N-[2-[(11R)-6-(2,6-Dimethylphenyl)-2,2,13-trioxo-11-[[1- (trifluoromethyl)cyclopropyl]methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12- yl]spiro[3.3]heptan-6-yl]carbamate (Compound 77) [00362] To a solution of 3-[[4-[(2R)-2-[[2-(tert-butoxycarbonylamino)spiro[3.3]heptan-6- yl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoy
  • the mixture was stirred at ambient temperature for 18 h.
  • the mixture was slowly added to a cold solution of HCl (65 mL of 12 M, 780.0 mmol) in water (8 L) over 30 min and the cream colored slurry was stirred at ambient temperature for 10 min.
  • the tan slurry was filtered using a M frit (slow filtration).
  • the precipitate was washed 3 times with 100 mL of water and air dried for 1 h.
  • the wet filter cake was dissolved in iPrOAc (3 L) and the water phase separated.
  • the organic phase was washed with 1 L of brine.
  • the aqueous phases were extracted with 500 mL of iPrOAc.
  • the combined organic phases were dried over magnesium sulfate, filtered over Celite and concentrated in vacuo.
  • the crude product was chromatographed on a 1.5 Kg column eluting with 20-70% EtOAc/hexanes (product eluted at 60% EtOAc). Pure fractions were concentrated. The fractions which contained some impurities were combined and concentrated.
  • the impure fractions were chromatographed on a 750 g column eluting with 30-65% EtOAc/hexanes. The product began to crystallize out during concentration and was dried in vacuo overnight.
  • the Impure product was diluted with 50 mL of EtOAc, seeded and allowed to stand overnight.
  • Step 4 tert-butyl ((2S,4s,6S)-6-((R)-1 6 -(2,6-dimethylphenyl)-3,3-dioxido-5-oxo-7-((1- (trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina- 4(1,3)-benzenacyclononaphane-6-yl)spiro[3.3]heptan-2-yl)carbamate, and tert-butyl ((2R,4r,6R)-6-((R)-1 6 -(2,6-dimethylphenyl)-3,3-dioxido-5-oxo-7-((1- (trifluoromethyl)cyclopropyl)methyl)-9-
  • Example 63 Preparation of Compound 80 Step 1: (R)-6-((2S,4s,6S)-6-Aminospiro[3.3]heptan-2-yl)-1 6 -(2,6-dimethylphenyl)-7- ((1-(trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina- 4(1,3)-benzenacyclononaphan-5-one 3,3-dioxide (Compound 80) [00369] (R)-6-((2S,4s,6S)-6-Aminospiro[3.3]heptan-2-yl)-1 6 -(2,6-dimethylphenyl)-7-((1- (trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)- benzenacyclononaphan-5
  • Example 64 Preparation of Compound 81 Step 1: (R)-6-((2R,4r,6R)-6-Aminospiro[3.3]heptan-2-yl)-1 6 -(2,6-dimethylphenyl)-7- ((1-(trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina- 4(1,3)-benzenacyclononaphan-5-one 3,3-dioxide (Compound 81) [00370] (R)-6-((2R,4r,6R)-6-Aminospiro[3.3]heptan-2-yl)-1 6 -(2,6-dimethylphenyl)-7-((1- (trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)- benzenacyclononaphan-5
  • Example 65 Preparation of Compound 82 Step 1: (R)-6-((2S,4s,6S)-6-(Benzylamino)spiro[3.3]heptan-2-yl)-16-(2,6- dimethylphenyl)-7-((1-(trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza- 1(2,4)-pyrimidina-4(1,3)-benzenacyclononaphan-5-one 3,3-dioxide [00371] (R)-6-((2S,4s,6S)-6-Aminospiro[3.3]heptan-2-yl)-1 6 -(2,6-dimethylphenyl)-7-((1- (trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)- benzenacyclononaphan-5-one 3,3
  • Step 2 (R)-1 6 -(2,6-Dimethylphenyl)-6-((2S,4s,6S)-6-(methylamino)spiro[3.3]heptan- 2-yl)-7-((1-(trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)- pyrimidina-4(1,3)-benzenacyclononaphan-5-one 3,3-dioxide [00372] (R)-6-((2S,4s,6S)-6-(Benzylamino)spiro[3.3]heptan-2-yl)-16-(2,6-dimethylphenyl)-7- ((1-(trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)- benzenacyclononaphan-5-one 3,3-dioxide [00
  • the product was combined with wet dihydroxypalladium (70 mg, 10% w/w, 0.4985 mmol) in a nitrogen purged flask and methanol (10 mL) was added.
  • hydrogen gas from a balloon was bubbled through the reaction mixture for 30 minutes, and the reaction was allowed to stir for an additional 2 hours at room temperature with the hydrogen balloon in place. After this time the reaction vessel was purged with nitrogen.
  • Example 66 Preparation of Compound 83 Step 1: (R)-6-((2R,4r,6R)-6-(Benzylamino)spiro[3.3]heptan-2-yl)-16-(2,6- dimethylphenyl)-7-((1-(trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza- 1(2,4)-pyrimidina-4(1,3)-benzenacyclononaphan-5-one 3,3-dioxide [00374] ((R)-6-((2R,4r,6R)-6-Aminospiro[3.3]heptan-2-yl)-1 6 -(2,6-dimethylphenyl)-7-((1- (trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)- benzenacyclononaphan-5-one
  • Step 2 (R)-1 6 -(2,6-Dimethylphenyl)-6-((2R,4r,6R)-6- (methylamino)spiro[3.3]heptan-2-yl)-7-((1-(trifluoromethyl)cyclopropyl)methyl)-9- oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)-benzenacyclononaphan-5-one 3,3- dioxide (hydrochloride salt) [00375] (R)-6-((2R,4r,6R)-6-(Benzylamino)spiro[3.3]heptan-2-yl)-16-(2,6-dimethylphenyl)- 7-((1-(trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)- benzenacyclononaphan-5-one 3,3-di
  • the product was combined with wet dihydroxypalladium (70 mg, 10% w/w, 0.4985 mmol) in a nitrogen purged flask and methanol (10 mL) was added. Hydrogen gas from a balloon was bubbled through the reaction mixture for 30 minutes, and the reaction was allowed to stir for an additional 2 hours at room temperature with the hydrogen balloon in place. After this time the reaction vessel was purged with nitrogen.
  • Example 68 Preparation of Compound 85 Step 1: N-((2R,4r,6R)-6-((R)-1 6 -(2,6-Dimethylphenyl)-3,3-dioxido-5-oxo-7-((1- (trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina- 4(1,3)-benzenacyclononaphane-6-yl)spiro[3.3]heptan-2-yl)acetamide (Compound 85) [00378] (R)-6-((2R,4r,6R)-6-aminospiro[3.3]heptan-2-yl)-1 6 -(2,6-dimethylphenyl)-7-((1- (trifluoromethyl)cyclopropyl)methyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)- benz
  • Example 69 Preparation of Compound 86 and Compound 87 Step 1: Methyl 7,10-dioxadispiro[3.1.46.14]undecane-2-carboxylate [00379] To a stirring solution of methyl 2-oxospiro[3.3]heptane-6-carboxylate (19.663 g, 116.91 mmol) and ethylene glycol (15.582 g, 14 mL, 251.05 mmol) in toluene (190 mL) at room temperature under ambient conditions was added p-toluenesulfonic acid hydrate (1.141 g, 5.9984 mmol).
  • the reaction mixture was heated to reflux (140 °C) with Dean-Stark apparatus for 24 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (350 mL). Two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate and concentrated to afford methyl 7,10-dioxadispiro[3.1.46.14]undecane-2-carboxylate (27.67 g, 100%) as pale-yellow oil. The product was carried to the next step without further purification.
  • Step 2 7,10-Dioxadispiro[3.1.46.14]undecan-2-yl(diphenyl)methanol
  • a stirring solution of methyl 7,10-dioxadispiro[3.1.46.14]undecane-2-carboxylate (27.67 g, 117.33 mmol) in anhydrous diethyl ether (250 mL) at 0 °C under nitrogen was dropwise added a solution of bromo(phenyl)magnesium (135 mL of 3 M, 405.00 mmol) in diethyl ether. During this addition, a copious amount of precipitate was formed.
  • reaction mixture was stirred at this temperature for 10 minutes.
  • the ice-water bath was removed, and the reaction mixture was heated to reflux (42 °C) for 2 hours.
  • the reaction mixture was cooled to 0 °C, and slowly quenched with saturated aqueous ammonium chloride (500 mL).
  • the reaction mixture was allowed to warm up to room temperature and stirred until all the solid has dissolved.
  • Two layers were separated, and the aqueous layer was extracted with diethyl ether (2 x 300 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate and concentrated.
  • Step 3 2-Benzhydrylidene-7,10-dioxadispiro[3.1.46.14]undecane [00381] To a stirring solution of 7,10-dioxadispiro[3.1.46.14]undecan-2-yl(diphenyl)methanol (28.07 g, 83.436 mmol) in toluene (400 mL) at room temperature under ambient conditions was added p-toluenesulfonic acid hydrate (1.664 g, 8.7479 mmol). The reaction mixture was heated to reflux (140 °C) with Dean-Stark apparatus for 24 hours. After cooling to room temperature, volatiles were removed under vacuum.
  • Step 4 7,10-Dioxadispiro[3.1.46.14]undecan-2-one
  • 2-benzhydrylidene-7,10-dioxadispiro[3.1.46.14]undecane (26.645 g, 83.682 mmol) in a mixture of acetonitrile (350 mL) and carbon tetrachloride (350 mL) at room temperature under ambient conditions was added water (550 mL).
  • ruthenium(III) chloride hydrate 1.902 g, 8.4367 mmol
  • sodium periodate 90.18 g, 421.61 mmol
  • reaction mixture was stirred at this temperature for 5 minutes.
  • the reaction mixture was heated to reflux (82 °C) for 1 hour.
  • the reaction mixture was allowed to cool down to room temperature and filtered through a pad of Celite.
  • the filter cake was washed with chloroform (3 x 200 mL).
  • the combined filtrate was concentrated under vacuum to remove the volatiles.
  • the residual aqueous layer was diluted with brine (200 mL), and the product was extracted with chloroform (3 x 400 mL).
  • the combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated.
  • Step 5 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-(7,10-dioxadispiro[3.1.46.14]undecan- 2-ylamino)-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00383] To a stirring suspension of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (8.656 g, 15.765 mmol) and 7,10-dioxadispiro[3.1.46.14]undecan-2-one (3.195 g, 18.996 mmol) in 1,2- dichloroethane (120 mL) at room temperature under ambient conditions was portionwise added sodium triacetoxyborohydride (10
  • reaction mixture was stirred at this temperature for 18 hours.
  • the reaction mixture was cooled to 0 °C, and slowly quenched with saturated aqueous ammonium chloride (400 mL).
  • Chloroform 150 mL was added to the cold mixture, and the reaction mixture was allowed to warm up to room temperature. Two layers were separated, and the aqueous layer was extracted with chloroform (2 x 200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate.
  • Step 6 (11R)-6-(2,6-Dimethylphenyl)-11-(2,2-dimethylpropyl)-12-(7,10- dioxadispiro[3.1.46.14]undecan-2-yl)-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one [00384] Into a solution of 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-2-(7,10- dioxadispiro[3.1.46.14]undecan-2-ylamino)-4,4-dimethyl-pentoxy]pyrimidin-2- yl]sulfamoyl]benzoic acid (8.57 g, 12.246 mmol) in anhydrous DMF (171 mL
  • the reaction was stirred at 60 °C in an oil bath for 20 hours. Another portion of pTSA hydrate (176 mg, 0.1645 mL, 0.9253 mmol) was added. The reaction was stirred for another 3 hours at 60 °C. The reaction was cooled to rt, and then it was concentrated under vacuum.
  • Step 3 tert-Butyl ((2S,4s,6S)-6-((R)-1 6 -(2,6-dimethylphenyl)-7-neopentyl-3,3- dioxido-5-oxo-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)- benzenacyclononaphane-6-yl)spiro[3.3]heptan-2-yl)carbamate (Compound 89), and tert-butyl ((2R,4r,6R)-6-((R)-1 6 -(2,6-dimethylphenyl)-7-neopentyl-3,3-dioxido-5-oxo- 9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)-benzenacyclononaphane-6- yl)spiro[3.3]heptan-2-yl)carbamate (
  • the cooling bath was removed, and the mixture stirred at ambient temperature for 24 h.
  • the mixture was slowly poured into a solution of HCl (8.0 mL of 12 M, 96.00 mmol) in water (900 mL) and stirred at ambient temperature for 10 min.
  • the tan slurry was filtered using a M frit.
  • the precipitate was washed 3x with 50 mL of water and air dried for 18 h.
  • the filter cake was dissolved in EtOAc (500 mL) and the water phase separated.
  • the aqueous phase was extracted with 300 mL of EtOAc and the combined organic phases were concentrated in vacuo.
  • Impure fractions were combined and chromatographed on a 450 g Reverse Phase column eluting with 50-100% ACN/Water to give tert-butyl N- ⁇ 6-[(11R)-6-(2,6- dimethylphenyl)-11-(2,2-dimethylpropyl)-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12-yl]spiro[3.3]heptan-2- yl ⁇ carbamate (14.3 g, 63%).
  • the reaction was cooled to -10 °C using an ice-salt bath then methyl chloroformate (465 ⁇ L, 6.018 mmol) was added.
  • the reaction mixture was allowed to stir at -10°C for 15 minutes and allowed to warm to rt. After stirring at rt for 1 h., the reaction mixture was evaporated to dryness then diluted with ethyl acetate then washed with 1N HCl (3x) and saturated NaCl solution.
  • the organic layer was isolated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • the crude material was purified by column chromatography on silica using 50-100% EtOAc/Hexanes gradient.
  • the cooling bath was removed, and the mixture stirred at ambient temperature for 36 hours.
  • the mixture was slowly poured into a solution of HCl (15 mL of 12 M, 180.0 mmol) in water (1.5 L) and stirred at ambient temperature for 10 min.
  • the tan slurry was filtered using an M frit.
  • the precipitate was washed 3X with 50 mL of water and air dried for 12 h.
  • the filter cake was dissolved in EtOAc (500 mL) and the water phase separated.
  • the aqueous phase was extracted with 300 mL of EtOAc and the combined organic phases were concentrated in vacuo affording a dark amber oil.
  • Step 2 (11R)-12-(6-Aminospiro[3.3]heptan-2-yl)-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one [00394] In a reaction vial, tert-butyl N-[2-[(11R)-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-12-yl]spiro[3.3]h
  • the reaction mixture was stirred at rt for 1.5 h. then evaporated to dryness.
  • the solid material was slurried in a mixture of 50% ethyl acetate/hexanes and filtered. The product was recovered as a white solid (HCl salt).
  • Step 3 Methyl ((2R,4r,6R)-6-((R)-1 6 -(2,6-dimethylphenyl)-7-neopentyl-3,3-dioxido- 5-oxo-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidina-4(1,3)-benzenacyclononaphane-6- yl)spiro[3.3]heptan-2-yl)carbamate (Compound 91) [00395] In a reaction vial, (11R)-12-(6-aminospiro[3.3]heptan-2-yl)-6-(2,6-dimethylphenyl)- 11-(2,2-dimethylpropyl)-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hex
  • the reaction was cooled to -10 °C using an ice-salt bath then methyl chloroformate (15.87 mg, 0.1679 mmol) was added.
  • the reaction mixture was allowed to stir at -10°C for 15 minutes, warmed to rt, concentrated to about half the volume.
  • the reaction mixture was diluted with ethyl acetate then washed with 1N HCl (3x) and saturated NaCl solution. The organic layer was isolated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • the crude material was purified using a normal phase SFC-MS method using a LUX-3 column (250 ⁇ 21.2mm, 5 ⁇ m particle size) sold by Phenomenex (pn: 00G-4493-P0-AX), and a dual gradient run from 10-40% mobile phase B over 14.5 minutes (includes 40-80% mobile phase rinsate).
  • Mobile phase A CO 2 .
  • Mobile phase B MeOH (20mM NH3).
  • Flow rate 10- 40% MeOH [20mM NH3] 60 mL/min, 40-80% MeOH [20mM NH3] 60 mL/min.

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Abstract

La présente invention concerne des modulateurs du régulateur de conductance transmembranaire de la fibrose kystique (CFTR) ayant la structure de noyau : , des compositions pharmaceutiques contenant au moins un tel modulateur, des procédés de traitement de maladies médiées par le CFTR, y compris la fibrose kystique, à l'aide de tels modulateurs et de telles compositions pharmaceutiques, des compositions pharmaceutiques combinées et des polythérapies, ainsi que des procédés et des intermédiaires pour fabriquer de tels modulateurs.
EP21814947.4A 2020-10-07 2021-10-06 Modulateurs du régulateur de conductance transmembranaire de la fibrose kystique Pending EP4225764A1 (fr)

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